Basic and Translational Research

Principal Investigators:

Hua Linda Cai, MD, PhD

For a full bibliography of Dr. Cai's publications, please click here.  A list of selected recent publications is below.

Jiang J, Huang K, Xu S, Garcia JGN, Wang C, Cai H. 2020. Targeting NOX4 alleviates sepsis-induced acute lung injury via attenuation of redox-sensitive activation of CaMKII/ERK1/2/MLCK and endothelial barrier dysfunction. Redox Biol. 2020;36:101638.

In summary, we have identified a novel, selective and causal role of NOX4 (versus other NOX isoforms) in inducing lung EC barrier dysfunction and injury/mortality in a preclinical CLP-induced septic model, which involves redox-sensitive activation of CaMKII/ERK1/2/MLCK pathway.

Cai H. (2020). Sex differences and smoking predisposition in patients with COVID-19. Lancet Respir Med. 2020;8(4):e20.

Cai H, Garcia JGN, Wang C. (2020). More to add to e-cigarette regulations: Unified approaches. Chest. 2020;157(4)771-773.

Zhang Y, Murugesan P, Huang K, Cai H. (2020). NADPH oxidases and oxidase crosstalk in cardiovascular diseases: Novel therapeutic targets. Nat Rev Cardiol. 2020;17(3):170-194.

The development of novel, effective and isoform-specific NOX inhibitors, as well as the development of novel strategies targeting uncoupled eNOS and mitochondrial dysfunction, are essential in realizing the therapeutic value of targeting NOX isoforms and downstream oxidase systems for the prevention and treatment of CVDs.

Li Q, Youn JY, Siu KL, Murugesan P, Zhang Y, Cai H. Knockout of dihydrofolate reductase in mice induces hypertension and abdominal aortic aneurysm via mitochondrial dysfunction. Redox Biol. 2019 Jun;24:101185. doi: 10.1016/j.redox.2019.101185. Epub 2019 Mar 29.

These data for the first time demonstrate that targeting DHFR-deficiency driven mitochondrial dysfunction may represent an innovative therapeutic option for the treatment of AAA and hypertension. 

Li H, Li Q, Zhang Y, Liu W, Gu B, Narumi T, Siu KL, Youn JY, Liu P, Yang X, Cai HNovel Treatment of Hypertension by Specifically Targeting E2F for Restoration of Endothelial Dihydrofolate Reductase and eNOS Function Under Oxidative Stress. Redox Biol. 2019 Jun;24:101185. doi: 10.1016/j.redox.2019.101185. Epub 2019 Mar 29.

These data for the first time demonstrate that targeting DHFR-deficiency driven mitochondrial dysfunction may represent an innovative therapeutic option for the treatment of AAA and hypertension. 

Hong Li , Qiang Li , Yixuan Zhang , Wenting Liu , Bo Gu , Taro Narumi , Kin Lung Siu , Ji Youn Youn , Peiqing Liu , Xia Yang , Hua Cai. Novel Treatment of Hypertension by Specifically Targeting E2F for Restoration of Endothelial Dihydrofolate Reductase and eNOS Function Under Oxidative Stress. Hypertension. 2019 Jan;73(1):179-189. doi: 10.1161/HYPERTENSIONAHA.118.11643.

Bioinformatic analyses confirmed a positive correlation between E2F1 and DHFR in human endothelial cells and arteries, and downregulation of both by oxidized phospholipids. In summary, endothelial DHFR is downregulated by H2O2 transcriptionally via an E2F-dependent mechanism, and that specifically targeting E2F1/2/3a to restore DHFR and eNOS function may serve as a novel therapeutic option for the treatment of hypertension.

Liu NM, Siu KL, Youn JY, Cai HAttenuation of neointimal formation with netrin-1 and netrin-1 preconditioned endothelial progenitor cells. J. Mol Med. 2017 95(3):335-348.

This article reports that chronic release of netrin-1 or injection of netrin-1 preconditioned endothelial progenitor cells (EPCs) remarkably attenuates neointimal formation and post-vascular endothelial injury. It indicates that netrin-1 and netrin-1 preconditioned EPCs can be used to effectively treat post-angioplasty coronary re-occlusion and restenosis, and points to a new way to manage the long-term complications of the angioplasty treatment of acute myocardial infarction.

Zhang Y, Li Q, Youn JY, Cai H. PTP1B in calpain-dependent feedback regulation of VEGFR2 in endothelial cells: implication in VEGF-dependent angiogenesis and diabetic wound healing. (2017) J. Biol. Chem. 13;292(2):407-416.

This article reports a novel calpain/PTP1B/VEGFR2 feedback regulation to prevent VEGFR2 over-activation. Activation of the primary calpain/PI3K/AMPK/Akt/eNOS signaling to induce NO production, or to attenuate PTP1B to potentiate VEGFR2 signaling, is highly effective in promoting diabetic wound healing.

Siu KL*, Li Q*, Zhang YX, Guo J, Youn JY, Du J, Cai H. NOX isoforms in the development of abdominal aortic aneurysm. (2017) Redox Biology. 11:118-125. *The authors contribute equally to this work.

This article reports novel roles and mechanisms of NADPH oxidase isoforms in mediating abdominal aortic aneurysm formation, through induction of eNOS uncoupling and vascular remodeling.

Zhang YX, Liu NM, Wang YC, Youn JY, Cai H. Endothelial cell calpain as a critical modulator of angiogenesis. (2017) BBA Mol. Basis of Disease. pii: S0925-4439(17)30108-4.

This article reviews novel signaling pathways and mechanisms underlying a critical role of endothelial cell calpain in the modulation of angiogenesis.

Zhang YX, Cai H. Endothelial to mesenchymal transition: When the good one goes bad. Editorial comments on “Endothelial to mesenchymal transition: A novel therapeutic target for cardiovascular diseases”. (2017) Trends in Cardiovasc Med.

This article is an editorial comment to discuss novel implications of endothelial to mesenchymal transition in the pathogenesis of cardiovascular diseases.

Mansoureh Eghbali, PhD

Lee LK, Medzikovic L, Eghbali M, Eltzschig HK, Yuan X. (2020). The Role of MicroRNAs in Acute Respiratory Distress Syndrome and Sepsis, From Targets to Therapies: A Narrative Review. Anesth Analg;131(5):1471-1484.

In this review, we discuss miRNAs that have been found to play a role in ARDS and sepsis, the potential mechanism of how particular miRNAs may contribute to the pathophysiology of ARDS, and strategies for pharmacologically targeting miRNA as therapy.

Medzikovic L, Cunningham CM, Li M, Amjedi M, Hong J, Ruffenach G, Eghbali M. (2020). Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19. J Mol Cell Cardiol;148:25-33.

In this review, we will provide a basic science perspective on current clinical observations in this rapidly evolving field and discuss the interplay sex differences, preexisting CVD and COVID-19-related cardiac injury.

Ruffenach G, Hong J, Vaillancourt M, Medzikovic L, Eghbali M. (2020). Pulmonary hypertension secondary to pulmonary fibrosis: clinical data, histopathology and molecular insights. Respir Res. 2020 Nov 18;21(1):303.

This review aims to provide a comprehensive translational overview of PH in PF patients from clinical diagnosis and outcome to the latest understanding of the histology and molecular pathophysiology of PF-PH.

Duhachek-Muggy S., Bhat K., Medina P., Cheng F., He L., Alli C., Saki M., Sree Muthukrishnan S.D., Ruffenach G., Eghbali M., Vlashi E., Pajonk F. (2020). Radiation Mitigation of the Intestinal Acute Radiation Injury in Mice by 1-[(4-Nitrophenyl)Sulfonyl]-4-Phenylpiperazine. Stem Cells Transl Med;9(1):106-119.

The objective of the study was to identify the mechanism of action for a radiation mitigator of the gastrointestinal (GI) acute radiation syndrome (ARS), identified in an unbiased high-throughput screen. 

Sulaiman D, Li J, Devarajan A, Cunningham CM, Li M, Fishbein GA, Fogelman AM, Eghbali M, Reddy ST. Paraoxonase 2 protects against acute myocardial ischemia-reperfusion injury by modulating mitochondrial function and oxidative stress via the PI3K/Akt/GSK-3β RISK pathway. J Mol Cell Cardiol. 2019 Apr;129:154-164. doi: 10.1016/j.yjmcc.2019.02.008. Epub 2019 Feb 23.

PON2 protects against acute myocardial IRI by reducing mitochondrial dysfunction and oxidative stress in cardiomyocytes via activation of the PI3K/Akt/GSK-3β RISK pathway.

Umar S., Li J., Hannabass K., Vaillancourt M., Cunningham CM, Moazeni S. Mahajan A, & Eghbali M. (2018). Free Fatty Acid Receptor GPR40 Mediates Lipid Emulsion-induced Cardioprotection. Anesthesiology:129(1):154-162. doi: 10.1097/ALN.0000000000002195. PMCID: PMC6084795.

This paper highlights the mechanisms of direct cardioprotective effects of lipid emulsion. More importantly, we have identified the key cell membrane receptor responsible of the effects of lipid emulsion in the heart.

Umar S., Cunningham C.M., Itoh Y., Moazeni S., Vaillancourt M., Sarji S. Centala A., Arnold A.P. & Eghbali M. (2018). The Y Chromosome Plays a Protective Role in Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine: 197(7):952-955. doi: 10.1164/rccm.201707-1345LE. PMID: 28934553.

The role of sex chromosomes in the development of pulmonary hypertension has not been studied in the past. We conducted the first investigation of the role of sex chromosomes, in the absence of gonadal hormones, in the development of hypoxia-induced PH using the unique Four Core Genotypes (FCG) and XY* mouse models. We found that the Y chromosome is protective against development of hypoxia-induced pulmonary hypertension in gonadectomized mice. UCLA newsroom:

Cunningham C.M., Eghbali M. (2018). An Introduction to Epigenetics in Cardiovascular Development, Disease, and Sexualization. Adv Exp Med Biol:1065:31-47. doi: 10.1007/978-3-319-77932-4_2.

This review summarizes the field of epigenetics in the context of cardiovascular development and disease while also highlighting the role of epigenetic regulation including DNA methylation, histone modification as well as non coding RNA-based regulation as powerful sources of sex differences within the cardiovascular system.  

 Saddic LA, Howard-Quijano K, Kipke J, Kubo Y, Dale EA, Hoover DB, Shivkumar K, Eghbali M., Mahajan A. (2018). Progression of myocardial ischemia leads to unique changes in immediate early gene expression in the spinal cord dorsal horn. Am J Physiol Heart Circ Physiol. doi: 10.1152/ajpheart.00337.2018. PMID: 30216122.

The pathological consequences of ischemic heart disease involve signaling through the autonomic nervous system. In this paper using acute and chronic myocardial ischemia in a large animal model of Yorkshire pigs, we identified genes that were differentially expressed in acute and chronic model compared to control in the thoracic dorsal horn using RNA-Seq analysis.

Barske J, Eghbali M, Kosarussavadi S, Choi E, Schlinger BA. (2018). The heart of an acrobatic bird. Comp Biochem Physiol A Mol Integr Physiol. pii: S1095-6433(18)30251-4. doi: 10.1016/j.cbpa.2018.10.010. PMID: 30367962.

In this paper we characterize the heart of an arobatic male (manakin) bird which has the highest heart rates during acrobatic courtship dance recorded in any bird or mammal. We found  the manakin heart had a significantly thicker left ventricular with a smaller left ventricular chamber as well as significantly greater gene expression of ryanodine receptors and androgen receptors. Testosterone treatment of non-breeding manakins increased gene expression of the Ca2+ pump SERCA.

Eran Halperin, PhD

Mandric I, Schwarz T, Majumdar A, Hou K, Briscoe L, Perez R, Subramaniam M, Hafemeister C, Satija R, Ye CJ, Pasaniuc B, Halperin E. (2020). Optimized design of single-cell RNA sequencing experiments for cell-type-specific eQTL analysis. Nat Commun. 2020 Oct 30;11(1):5504.

We provide a practical approach on selecting cost-effective designs for maximizing cell-type-specific eQTL power which is available in the form of a web tool.

Goodman-Meza D, Rudas A, Chiang JN, Adamson PC, Ebinger J, Sun N, Botting P, Fulcher JA, Saab FG, Brook R, Eskin E, An U, Kordi M, Jew B, Balliu B, Chen Z, Hill BL, Rahmani E, Halperin E, Manuel V. (2020). A machine learning algorithm to increase COVID-19 inpatient diagnostic capacity. PLoS One. 2020 Sep 22;15(9):e0239474.

We found that our machine learning algorithm had excellent diagnostic metrics compared to SARS-CoV-2 PCR. This ensemble machine learning algorithm to diagnose COVID-19 has the potential to be used as a screening tool in hospital settings where PCR testing is scarce or unavailable.

Miao Z, Alvarez M, Ko A, Bhagat Y, Rahmani E, Jew B, Heinonen S, Muñoz-Hernandez LL, Herrera-Hernandez M, Aguilar-Salinas C, Tusie-Luna T, Mohlke KL, Laakso M, Pietiläinen KH, Halperin E, Pajukanta P. (2020). The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance. PLoS Genet. 2020 Sep 14;16(9):e1009018.

We demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals’ adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

Martino C, Shenhav L, Marotz CA, Armstrong G, McDonald D, Vázquez-Baeza Y, Morton JT, Jiang L, Dominguez-Bello MG, Swafford AD, Halperin E, Knight R. (2020). Context-aware dimensionality reduction deconvolutes gut microbial community dynamics. Nat Biotechnol. 2020 Aug 31. [Epub ahead of print].

To address these challenges simultaneously, we developed compositional tensor factorization (CTF), which allows an unsupervised dimensionality reduction for repeated measures data, producing both a traditional beta-diversity analysis as well as a differential feature abundance assessment.

Alvarez M, Rahmani E, Jew B, Garske KM, Miao Z, Benhammou JN, Ye CJ, Pisegna JR, Pietiläinen KH, Halperin E, Pajukanta P. (2020). Enhancing droplet-based single-nucleus RNA-seq resolution using the semi-supervised machine learning classifier DIEM. Sci Rep. 2020 Jul 3;10(1):11019.

Our novel method DIEM removes debris-contaminated droplets from single-cell-based data fast and effectively, leading to cleaner downstream analysis. 

Mandric I, Hill BL, Freund MK, Thompson M, Halperin E. (2020). BATMAN: Fast and Accurate Integration of Single-Cell RNA-Seq Datasets via Minimum-Weight Matching. iScience. 2020 Jun 26;23(6):101185.

Across multiple simulations and real datasets, we show that our method significantly outperforms state-of-the-art tools with respect to existing metrics for batch effects by up to 80% while retaining cell-to-cell relationships.

Joseph TA, Shenhav L, Xavier JB, Halperin E, Pe'er I. (2020). Compositional Lotka-Volterra describes microbial dynamics in the simplex. PLoS Comput Biol. 2020 May 29;16(5):e1007917.

We investigate when information about direct effects can be recovered from relative data that naively provide information about only indirect effects. Our results suggest that strong effects may be recoverable from relative data, but more subtle effects are challenging to identify.

Agrawal A, Chiu AM, Le M, Halperin E, Sankararaman S. (2020). Scalable probabilistic PCA for large-scale genetic variation data. PLoS Genet. 2020 May 29;16(5):e1008773.

To illustrate the utility of computing PCs in large samples, we leveraged the population structure inferred by ProPCA within White British individuals in the UK Biobank to identify several novel genome-wide signals of recent putative selection including missense mutations in RPGRIP1L and TLR4.

Jew B, Alvarez M, Rahmani E, Miao Z, Ko A, Garske KM, Sul JH, Pietiläinen KH, Pajukanta P, Halperin E. (2020). Accurate estimation of cell composition in bulk expression through robust integration of single-cell information. Nat Commun. 2020 Apr 24;11(1):1971.

We present Bisque, a tool for estimating cell type proportions in bulk expression. Bisque implements a regression-based approach that utilizes single-cell RNA-seq (scRNA-seq) or single-nucleus RNA-seq (snRNA-seq) data to generate a reference expression profile and learn gene-specific bulk expression transformations to robustly decompose RNA-seq data.

Andrew Hudson, MD, PhD

Hudson AE. (2020). Anesthesia as Decoupling? Anesthesiology. 2020 Jul;133(1):11-12.

The authors are able to address a question that is currently unfeasible in mammalian models: do general anesthetics equally disrupt relationships between all neurons, or are connections between particular functional networks critical vulnerable nodes that are responsible for the behavioral impact of general anesthetics?

Igor V. Ovchinnikov, Wenyuan Li, Yuquan Sun, Andrew E. Hudson, Karlheinz Meier, Robert N. Schwartz and Kang L. Wang. Criticality or Supersymmetry Breaking? Symmetry 2020, 12(5), 805;

In many stochastic dynamical systems, ordinary chaotic behavior is preceded by a full-dimensional phase that exhibits 1/f-type power spectra and/or scale-free statistics of (anti)instantons such as neuroavalanches, earthquakes, etc. In contrast with the phenomenological concept of self-organized criticality, the recently found approximation-free supersymmetric theory of stochastics (STS) identifies this phase as the noise-induced chaos (N-phase), i.e., the phase where the topological supersymmetry pertaining to all stochastic dynamical systems is broken spontaneously by the condensation of the noise-induced (anti)instantons. Here, we support this picture in the context of neurodynamics.

Hudson AE, Ma Li, Liu Wentai. Propofol Anesthesia Increases Long-range Frontoparietal Corticocortical Interaction in the Oculomotor Circuit in Macaque Monkeys. Anesthesiology 2019 April, Vol.130, 560-571. doi: 10.1097/ALN.0000000000002637

Propofol anesthesia induces coherent oscillations and increases certain frontoparietal interactions in oculomotor cortices. Frontal eye field and lateral intraparietal area show increased coherence and phase-amplitude coupling. Visual areas 2 and 1, which have similar anatomic projection patterns, show similar increases in phase-amplitude coupling, suggesting higher order feedback increases in influence during propofol anesthesia relative to wakefulness. This suggests that functional connectivity between frontal and parietal areas is not uniformly decreased by anesthetics.

Hudson AE, Mashour George. General Anesthesia and the Cortex: Communication Breakdown? Anesthesiology 2019 April, Vol. 130, 526-527. doi:10.1097/ALN.0000000000002636 

This report is about the study of a specific neurophysiologic relationship across the oculomotor circuit—a well-defined and structurally connected tract from the frontal cortex to parietal cortex—on the surface of the primate brain. They find, contrary to what would be predicted based on past studies in humans and rodents, that propofol increases long-range functional coupling of neural activity across this frontal–parietal circuit. Their work prompts the question of whether general anesthesia really is a state of communication breakdown across the cortex and what the implications are for clinical monitoring.

Hudson AE, Metastability of Neuronal Dynamics During General Anesthesia: Time for a Change in Our Assumptions? Front Neural Circuits 2017 August 25:11:58 doi: 10.3389/fncir.2017.00058

This hypothesis and theory article begins from the observation that different anesthetic agents produce stereotyped signatures in the electroencephalogram (EEG), which may vary with dose, yet how brain activity transitions between these different EEG signatures in time remains understudied. Data in rats anesthetized with isoflurane suggests that brain activity alternates between multiple states, often spending on the order of 2-10 min in one state before shifting to another, even without a stimulus or change in the anesthetic. This suggests the hypothesis that brain state is metastable during anesthesia: though it appears that the brain is at equilibrium on short timescales (on the order of seconds to a few minutes), longer intervals show shifting behavior. If metastability exists during anesthesia, it implies that there is not a one-to-one mapping between the brain state, as reported by the EEG, and the effect site concentration of the anesthetic drug. This could explain difficulties encountered with depth of anesthesia monitors and should force a rethinking of the notion of depth of anesthesia as a single dimension. 

Hudson AE, Pryor KO. Integration and Information: Anesthetic Unconsciousness Finds a New Bandwidth. Anesthesiology 2016 Nov;125(5). doi:10.1097/ALN.0000000000001344

The unconsciousness reliably and reversibly produced by anesthetics provides insight into one of the great questions in all of science: what are the necessary and sufficient mechanistic features of how humans are conscious? One robust feature of anesthetic unconsciousness, whether assessed by electrophysiology or neuroimaging, is the fragmentation, or functional disconnection, of different cortical areas. Yet, upon recovery from anesthesia, we remain ourselves, with largely intact memories, experiences, and personalities, suggesting that the brain’s structural connectivity, or wiring, is stable during anesthesia. So fragmentation results from reversible disruption of this connectivity. This editorial by Dr. Hudson highlights a paper by Pal et al. in this issue of Anesthesiology that characterizes the cholinergic system’s involvement in cortical fragmentation with anesthesia.

Hudson AE, Hemmings HC Jr, Kuck K. Pharmacokinetics and pharmacodynamics of inhaled anesthetics. In: Hemmings and Egan. Anesthetic pharmacology, 2nd ed. Elsevier: NY (In Press).

This chapter begins with the history of inhaled agents for anesthesia before delving into how the drugs move through the body (pharmacokinetics) and the effects of the drugs and how they work (pharmacodynamics) are introduced, to be covered more in depth in the chapter on “Pharmacology of inhaled anesthetics”. Classes of anesthetics, their physical properties, and potency are reviewed. The uptake, distribution, metabolism, and degradation of inhaled agents, with special emphasis on issues associated with inhaled agent delivery (as opposed to intravenous delivery) are covered. The chapter closes with emerging developments in the delivery of anesthetic agents, including intravenous delivery of volatile agents, and the use of volatile anesthetics in the intensive care unit.

Hudson AE, Kuck, K. Pharmacology of inhaled anesthetics. In: Hemmings and Egan. Anesthetic pharmacology, 2nd ed. Elsevier: NY (In Press).

This chapter begins with general coverage of the history of inhaled anesthetics, the relationship between their structure and activity and history behind the studies of their mechanisms of action. Coverage of individual agents includes nonanesthetic effects, adverse effects, and a general taxonomy based upon predominant action at the GABAA receptor or the NMDA receptor. Interactions of drugs and factors that influence the Minimum Alveolar Concentration (MAC), or potency, are covered, together with common clinical considerations that might drive particular choices of agents during clinical care.  The chapter closes with a review of emerging developments, including developmental neurotoxicity, the relationship between anesthesia and neurodegenerative disease, neuroinflammation and cognitive dysfunction, anesthetic sensitivity and mortality, anesthetic preconditioning, immune modulation and cancer, closed loop delivery systems, and pharmacologic reanimation to reverse the anesthetic state.

Rajesh Kumar, PhD

Choi SE, Roy B, Freeby M, Mullur R, Woo MA, Kumar R. Prefrontal Cortex Brain Damage and Glycemic Control in Patients With Type 2 Diabetes. J Diabetes. 2020; 12(6):465-473. doi: 10.1111/1753-0407.13019. Epub 30 Dec 2019.

This study examined brain tissue integrity in sites that controls cognition (prefrontal cortices; PFC) and its relationships to glycemic outcomes in adults with type 2 diabetes mellitus (T2DM).

Choi S, Roy B, Kumar R, Fonarow GC, Woo MA. Heart Failure Self-care Associated With Brain Injury in Executive Control Regions. J Cardiovasc Nurs. 2019; 34(6):433-439. doi: 10.1097/JCN.0000000000000611. Nov/Dec 2019.

Inadequate self-care is linked to poor health outcomes in heart failure (HF). Self-care depends on decision-making abilities, but links between self-care and brain injury to executive decision-making regulatory areas (prefrontal cortices) are unclear. We investigated the relationships between HF self-care and status of prefrontal cortices.

Allen LA, Harper RM, Guye M, Kumar R, Ogren JA, Vos SB, Ourselin S, Scott CA, Lhatoo SD, Lemieux L, Diehl B. Altered Brain Connectivity in Sudden Unexpected Death in Epilepsy (SUDEP) Revealed Using Resting-State fMRI. Neuroimage Clin. 2019; 24:102060. doi: 10.1016/j.nicl.2019.102060. Epub 2019 Oct 28.

The circumstances surrounding SUDEP suggest autonomic or respiratory collapse, implying central failure of regulation or recovery. Characterisation of the communication among brain areas mediating such processes may shed light on mechanisms and noninvasively indicate risk. We used rs-fMRI to examine network properties among brain structures in people with epilepsy who suffered SUDEP (n = 8) over an 8-year follow-up period, compared with matched high- and low-risk subjects (n = 16/group) who did not suffer SUDEP during that period, and a group of healthy controls (n = 16).

Song X, Roy B, Lai M, Sahib A, Fonarow GC, Woo MA, Kumar R. Aberrant Brain Functional Connectivity Dynamic Responses to the Valsalva Maneuver in Heart Failure. J Card Fail. 2019; 25(9):757-766. doi: 10.1016/j.cardfail.2019.06.010. Epub 2019 Sep.

Patients with heart failure (HF) show abnormal autonomic activities, which may stem from altered functional connectivity (FC) between different brain sites. We evaluate insular and cerebellar FC with other brain areas, before, during, and after the Valsalva challenge, with functional magnetic resonance imaging in 35 HF and 35 control subjects. Significant insular FC emerged with striatum, thalamus, and anterior cingulate. 

Cabrera-Mino C, Roy B, Woo MA, Singh S, Moye S, Halnon NJ, Lewis AB, Kumar R, Pike NA. Reduced Brain Mammillary Body Volumes and Memory Deficits in Adolescents Who Have Undergone the Fontan Procedure. Pediatr Res. 2020; 87(1):169-175. doi: 10.1038/s41390-019-0569-3. Epub 2019 Sep 9.

Adolescents with single ventricle heart disease (SVHD) who have undergone the Fontan procedure show cognitive/memory deficits. Mammillary bodies are key brain sites that regulate memory; however, their integrity in SVHD is unclear. We evaluated mammillary body (MB) volumes and their associations with cognitive/memory scores in SVHD and controls.

Singh S, Roy B, Pike N, Daniel E, Ehlert L, Lewis AB, Halnon N, Woo MA, Kumar R. Altered Brain Diffusion Tensor Imaging Indices in Adolescents With the Fontan Palliation. Neuroradiology. 2019; 61(7):811-824. doi: 10.1007/s00234-019-02208-x. Epub 30 April 2019.

Single ventricle heart disease (SVHD) patients show injury in brain sites that regulate autonomic, mood, and cognitive functions. However, the nature (acute or chronic changes) and extent of brain injury in SVHD are unclear. Our aim was to examine regional brain tissue damage in SVHD over controls using DTI-based mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) procedures.

Allen LA, Vos SB, Kumar R, Ogren JA, Harper RK, Winston GP, Balestrini S, Wandschneider B, Scott CA, Ourselin S, Duncan JS, Lhatoo SD, Harper RM, Diehl B. Cerebellar, Limbic, and Midbrain Volume Alterations in Sudden Unexpected Death in Epilepsy. Epilepsia. 2019; 60(4):718-729. doi: 10.1111/epi.14689. Epub 14 March 2019.

The processes underlying sudden unexpected death in epilepsy (SUDEP ) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk.

Singh S, Kumar R, Roy B, Woo MA, Lewis A, Halnon N, Pike N. Regional brain gray matter changes in adolescents with single ventricle heart disease. Neurosci Lett. 2018 Feb 5.

Adolescents with single ventricle heart disease show autonomic, mood, and cognitive deficits suggesting aberrations in brain areas regulating these functions. Subjects were found to show compromised gray matter integrity in areas responsible for controlling these functions. These findings indicate frequent deficits found in SVHD subjects have a brain structural basis in the condition.

Pike NA, Roy B, Gupta R, Singh S, Woo MA, Halnon NJ, Lewis AB, Kumar R. Brain abnormalities in cognition, anxiety, and depression regulatory regions in adolescents with single ventricle heart disease. J Neurosci Res. 2018 Jun.

Adolescents with single ventricle heart disease show cognitive impairments and anxiety and depressive symptoms indicating brain injury to areas responsible for these functions. Subjects with SVHD were found to show brain injury in areas controlling cognition, anxiety, and depression with variable male-female differences. These findings may contribute to functional deficits found in the condition.

Song X, Roy B, Fonarow GC, Woo MA, Kumar R. Brain structural changes associated with aberrant functional responses to the Valsalva maneuver in heart failure. J Neurosci Res. 2018 Sep.

We evaluated the correlations between brain structural injury and functional timing and magnitude of neural signal patterns within autonomic control brain areas in heart failure patients. We found the impaired functional responses of insular and cerebellar sites are correlated with the severity of tissue changes. These findings strengthen our understanding of brain structural and functional alterations underlying impaired autonomic regulations in heart failure subjects.

Song X, Roy B, Kang DW, Aysola RS, Macey PM, Woo MA, Yan-Go FL, Harper RM, Kumar R. Altered resting-state hippocampal and caudate functional networks in patients with obstructive sleep apnea. Brain Behav. 2018 Jun.

The aim of the study was to examine resting-state functional connectivity (FC) of the hippocampus and caudate to other brain areas in OSA relative to control subjects, and to relate these changes to behavioral and neuropsychological variables. Results showed that altered limbic-striatal-cortical FC in OSA were correlated with mood and cognitive symptoms in OSA. These findings indicate further understanding into the neural mechanisms underlying the comorbidity of mood and cognitive deficits in OSA.

Kheirandish-Gozal L, Sahib AK, Macey PM, Philby MF, Gozal D, Kumar RRegional brain tissue integrity in pediatric obstructive sleep apnea. Neurosci Lett. 2018 Aug 24.

Children with obstructive sleep apnea exhibit signs of neural injury and functional deficits in areas responsible for behavior and cognitive regulation shown through altered behavioral and cognitive performance. These subjects show acute tissue injury in neural regions associated with autonomic, respiratory, cognitive, and neuropsychologic control. These findings may contribute to regional brain tissue integrity changes in pediatric OSA.

Luo Y, Abiri P, Zhang S, Chang CC, Kaboodrangi AH, Li R, Sahib AK, Bui A, Kumar R, Woo M, Li Z, Packard RRS, Tai YC, Hsiai TK. Non-Invasive Electrical Impedance Tomography for Multi-Scale Detection of Liver Fat Content. Theranostics. 2018 Feb 8.

Magnetic Resonance Imaging is normally used to detect fatty liver, with nonalcoholic fatty liver disease being a common problem in obesity. This study looks at a low cost and portable electrical impedance tomography (EIT) approach with circumferential abdominal electrodes for liver conductivity measurements. The preliminary findings provide theoretical and experimental framework for a multi-scale EIT strategy to detect liver lipid content.

Macey PM, Haris N, Kumar R, Thomas MA, Woo MA, Harper RM. Obstructive sleep apnea and cortical thickness in females and males. PLoS One. 2018 Mar 6.

Obstructive sleep apnea affects a significant amount of the adult population, with alterations in white and gray matter. Studies indicate sex-specific psychological and physiological changes in white matter with greater injury in females than male subjects. Reduced cortical thickness was found and represents tissue atrophy from long term injury, with greater cortical injury in cognitive areas of female OSA patients. This cortical thinning in male and female OSA patients may contribute to autonomic dysregulation and impaired upper airway sensori-motor function.

Macey PM, Kheirandish-Gozal L, Prasad JP, Ma RA, Kumar R, Philby MF, Gozal D. Altered Regional Brain Cortical Thickness in Pediatric Obstructive Sleep Apnea. Front Neurol. 2018 Jan 22.

Obstructive sleep apnea affects a significant population of children and is found to be associated with cognitive and behavioral deficits. This study found significant changes in cortical thickness in children with obstructive sleep apnea which likely contributes to the cognitive and behavioral dysfunction frequently found in pediatric OSA.

Riccardo Olcese, PhD

Zyrianova T, Lopez B, Olcese R, Belperio J, Waters CM, Wong L, Nguyen V, Talapaneni S, Schwingshackl A. (2020). K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury. Sci Rep. 2020 Dec 15;10(1):22011.

We report for the first time the functional expression of TREK- 1K+ channels on primary alveolar epithelial cells.

Zyrianova T, Lopez B, Liao A, Gu C, Wong L, Ottolia M, Olcese R, Schwingshackl A. (2020). BK Channels Regulate LPS-induced CCL-2 Release from Human Pulmonary Endothelial Cells. Am J Respir Cell Mol Biol. 2020 Nov 20. [Epub ahead of print].

In this study, we provide the first evidence for the expression of functional BK channels (pore-forming α1 subunit KCNMA1 and the auxiliary KCNMB1, -3, -4 β-subunits) in human microvascular endothelial cells and in primary human alveolar epithelial cells by demonstrating pharmacological hyperpolarization with two BK activators (NS1619 and NS19504), and propose a potential role for BK channels in LPS-induced cytokine secretion.

Pantazis A, Kaneko M, Angelini M, Steccanella F, Westerlund AM, Lindström SH, Nilsson M, Delemotte L, Saitta SC, Olcese R. (2020). Tracking the motion of the KV 1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy. J Physiol. 2020 Nov;598(22):5245-5269.

We propose a mechanism of epileptogenesis based on enhanced KV1.2 inactivation leading to increased synaptic release preferentially in excitatory neurons, and hence the perturbation of the excitatory/inhibitory balance of neuronal circuits.

Landaw J, Zhang Z, Song Z, Liu MB, Olcese R, Chen PS, Weiss JN, Qu Z. (2020). Small-conductance Ca2+-activated K+ channels promote J-wave syndrome and phase 2 reentry. Heart Rhythm. 2020 Sep;17(9):1582-1590.

The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca2+ channels in promoting J-wave syndrome and ventricular arrhythmias.

Venugopal, S, Seki S, Terman DH, Pantazis A, Olcese R, Wiedau-Pazos, M, Chandler, SH. Resurgent Na+ Current Offers Noise Modulation in Bursting Neurons. PLoS Comput Biol. 2019 Jun 21;15(6):e1007154. doi: 10.1371/journal.pcbi.1007154. [Epub ahead of print]

Model analysis further predicted a negative feedback loop between the persistent and resurgent gating variables which mediate such gain in burst stability. These results highlight a novel role for the voltage-gated resurgent Na+ componenet in moderating the entropy of burst-encoded neural information.

Pantazis A, Westerberg K, Althoff T, Abramson J, Olcese R. Harnessing photoinduced electron trasnfer to optically determine protein sub-nanoscale atomic distances. Nat Commun. 2018 Nov 9;9(1):4738. doi: 10.1038/s41467-018-07218-6. 

We report the first implementation of DEPET on human large-conductance K+ (BK) channels under voltage clamp. We describe conformational rearrangements underpinning BK channel sensitivity to electrical excitation, in conducting channels expressed in living cells. Finally, we validate DEPET in synthetic peptide length standards, to evaluate its accuracy in measuring sub- and near-nanometer intramolecular distances.

Savalli N*, Pantazis A, Sigg D, Weiss JN, Neely A, Olcese R. The α2δ-1 subunit remodels CaV1.2 voltage sensors and allows Ca2+ influx at physiological membrane potentials. J Gen Physiol. 2016;148(2):147-59 PMCID: PMC4969795. (Recommended by "Faculty of 1000 Prime", *Awarded 2017 Cranefield Award for this work)

Voltage-activated ion channels, are largely responsible for cell electrical excitability. They “sense” the electric potential across the plasmamembrane using specialized Voltage Sensing Domains that compel the pore to open it. By optically tracking the movement of a human calcium channel using a technique called Voltage Clamp fluorometry, the Olcese laboratory revealed the mechanism by which one accessory proteins (called a2d-1) increases the sensitivity of the channel to membrane depolarizations, thus allowing the channel to operate at physiological potentials. This work has been highlighted by a Commentary in the same issue of the Journal of General Physiology, and by Dr. A. C. Dolphin who recommended the work as being of special significance in the Faculty of 1000 Prime.

Balderas E, Torres NS, Rosa-Garrido M, Chaudhuri D, Toro L, Stefani E, Olcese R. MitoBKCa channel is functionally associated with its regulatory β1 subunit in cardiac mitochondria. J Physiol. 2019 Jun 7. doi: 10.1113/JP277769. [Epub ahead of print]

The reduced activity of mitoBKCa was accompanied with a high expression of BKCa transcript in the BK-β1 KO, suggesting less abundance of mitoBKCa channels in this genotype. Accordingly, BK-β1subunit increased two-fold the localization of BKDEC (the splice variant of BKCathat specifically targets mitochondria) into mitochondria. Importantly, both paxilline treated and BK-β1 KO mitochondria displayed a more rapid Ca2+ overload, featuring an early opening of the mitochondrial transition pore (mPTP). We provide strong evidence that mitoBKCaassociates with its regulatory BK-β1 subunit in cardiac mitochondria, ensuring proper targeting and activation of the mitoBKCa channel helps to maintain mitochondrial Ca2+ homeostasis.

Michela Ottolia, PhD

Scranton K, John S, Escobar A, Goldhaber JI, Ottolia M. (2020). Modulation of the cardiac Na+-Ca2+exchanger by cytoplasmic protons: Molecular mechanisms and physiological implications. Cell Calcium. 2020 May;87:102140.

This review summarizes the recent progress towards the understanding of the molecular mechanisms underlying the ionic regulation of the cardiac NCX with special emphasis on pH modulation and its physiological impact on the heart.

Yue X, Hazan A, Lotteau S, Zhang R, Torrente AG, Philipson KD, Ottolia M, Goldhaber JI. (2020). Na/Ca exchange in the atrium: Role in sinoatrial node pacemaking and excitation-contraction coupling. Cell Calcium. 2020 May;87:102167.

Using a novel atrial-specific NCX1 KO mouse, we found unexpected changes in atrial cell morphology and calcium handling, together with dramatic alterations in the function of sinoatrial node (SAN) pacemaker activity. In this review, we will discuss these findings and their implications for cardiac disease.

Soban Umar, MD, PhD

Ruffenach G., O’Connor E., Vaillancourt M., Jason Hong J., Cao N., Sarji S., Moazeni S., PapeshJ., Grijalva V., Cunningham C.M., Shu L., Chattopadhyay A., Tiwari S., Mercier O., Perros F.,Umar S., Yang X., Gomes A.V., Fogelman A., Reddy S.T. & Eghbali M. (2020). Oral 15-HETE Induces Pulmonary Hypertension in Mice by Triggering T-cell Dependent Endothelial Cell Apoptosis. In Press: Hypertension;76(3):985-996.

Our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell–dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.

Anwar A, Seger C, Tollefson A, Diachun CAB, Tanaka P, Umar S. (2020). Medical education in the COVID-19 era: Impact on anesthesiology trainees. J Clin Anesth. 2020 Nov;66:109949.

Hong J, Arneson D, Umar S, Ruffenach G, Cunningham CM, Ahn IS, Diamante G, Bhetraratana M, Park JF, Said E, Huynh C, Le T, Medzikovic L, Humbert M, Soubrier F, Montani D, Girerd B, Trégouët DA, Channick R, Saggar R, Eghbali M., Yang X. (2020). Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning. Am J Respir Crit Care Med. 2020 Oct 6. [Epub ahead of print]

 Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.

Bae DJ, Tehrani DM, Rabadia SV, Frost M, Parikh RV, Calfon-Press M, Aksoy O, Umar S, Ardehali R, Rabbani A, Bokhoor P, Nsair A, Currier J, Tobis J, Fonarow GC, Dave R, Rafique AM. (2020). Angiotensin Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use Among Outpatients Diagnosed With COVID-19. Am J Cardiol. 2020 Oct 1;132:150-157.

In conclusion, among patients who were diagnosed with COVID-19, ACEI/ARB use was not associated with increased risk of hospital admission.

Park JF, Banerjee S, Umar S. (2020). In the eye of the storm: the right ventricle in COVID-19. Pulm Circ. 2020 Jul-Sep;10(3):2045894020936660.

In conclusion, the unique pathophysiology of COVID-19 places the RV at higher risk of failure.

Seger CD, Wang L, Dong X, Tebon P, Kwon S, Liew EC, Marijic J, Umar S, Hoftman NN. (2020). A Novel Negative Pressure Isolation Device for Aerosol Transmissible COVID-19. Anesth Analg. 2020 Sep;131(3):664-668.

In this report, we describe the development and testing of a disposable containment chamber that protects HCWs from contact with droplets and dispersed aerosols released by a patient during airway management.

Aryan L, Younessi D, Zargari M, Banerjee S, Agopian J, Rahman S, Borna R, Ruffenach G, Umar S, Eghbali M. (2020). The role of estrogen receptors in cardiovascular diseases. International Journal of Molecular Sciences;21(12):4314.

This review will discuss current reports on the underlying molecular mechanisms of the ERs in regulating vascular pathology, with a special emphasis on hypertension, pulmonary hypertension, and atherosclerosis, as well as in regulating cardiac pathology, with a particular emphasis on ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.

Aryan L., Medzikovic L., Umar S., Eghbali M. (2020). Pregnancy-Associated Cardiac Dysfunction and the Regulatory Role of microRNAs. Biology of Sex Differenecs;11(1):14.

This review will summarize current reports on pregnancy-related cardiovascular complications that may lead to cardiac dysfunction and HF during and after pregnancy in previously healthy women, with a focus on the pathophysiological role of miRNAs.

Umar S., Ruffenach G., Moazeni S., Vaillancourt M., Hong J., Cunningham C.M., Cao N., NavabS., Sarji S., Li M., Lee L., Fishbein G., Ardehali A., Navab M., Reddy S.T., Eghbali M. (2020).Involvement of Low Density Lipoprotein Receptor in the Pathogenesis of Pulmonary Hypertension. J Am Heart Assoc;9(2):e012063.

Human PH is associated with decreased LDL-R in lungs and increased oxidized LDL in lungs and plasma. WD-fed LDL-R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL-R and oxidized lipids in PH.

Anjum Anwar,Christian Seger, Ashley Tollefson, Carol Ann B. Diachun, Pedro Tanaka, and Soban Umar. Medical education in the COVID-19 era: Impact on anesthesiology trainees. Epub 2020 Jun 1. doi: 10.1016/j.jclinane.2020.109949.

 Although COVID-19 has perturbed Graduate Medical Education (GME) in all specialties, hands-on disciplines (including Anesthesiology) have been affected the most. Herein we briefly explore the impact of COVID-related changes on Anesthesiology training.

Razee A, Umar S. (2020). Pulmonary Artery Denervation for Pulmonary Hypertension: Recent Updates and Future Perspectives. Trends Cardiovasc Med. 2020 May 17. [Epub ahead of print]

Vaillancourt M, Chia P, Medzikov L, Ruffenach G, Younessi D, Umar S. Experimental Pulmonary Hypertension is Associated with Neuroinflammation in the Spinal Cord. Front. Physiol. 10:1186. doi: 10.3389/fphys.2019.01186.  Online publication 20 September 2019:

It is possible to hypothesize a possible role for lung inflammation and RV dysfunction in triggering and/or sustaining the neuroinflammation seen in the thoracic spinal cord of our rats with PH. The authors report for the first time evidence for the presence of neuroinflammation in the thoracic spinal cord of pulmonary hypertensive rats. Whether this neuroinflammation is triggered and/or sustained by lung inflammation and RV dysfunction, as well as its potential impact on cardiopulmonary function remains elu\. 

Le T, Makar C, Morway P, Hoftman N, Umar S. Pulmonary artery denervation: a novel treatment modality for pulmonary hypertension. J Thorac Dis. 2019 Apr;11(4):1094-1096. doi: 10.21037/jtd.2019.02.93.

The evidence for SNS and RAAS activation in various forms of pulmonary hypertension is convincing and could serve as a common therapeutic target. A direct, targeted, and minimally invasive procedure such as pulmonary artery denervation offers a novel therapeutic option for the treatment of PH. Whether these procedures are superior to the standard of care pharmacologic therapies for PH is still debatable. The efficacy and safety of such procedures remains to be established in the long term.

Umar S, Li J, Hannabass K, Vaillancourt M, Cunningham C, Moazeni S, Mahajan A, Eghbali M. Free Fatty Acid Receptor G-protein-coupled Receptor 40 Mediates Lipid Emulsion-induced Cardioprotection. Anesthesiology. 2018 April. doi: doi:10.1097/ALN.0000000000002195 Epub 2018 April 3 PMID: 29620570

This paper highlights the mechanisms of direct cardioprotective effects of lipid emulsion. More importantly, we have identified the key cell membrane receptor responsible of the effects of lipid emulsion in the heart.

Umar S, Cunningham CM, Itoh Y, Moazeni S, Vaillancourt M, Sarji S, Centala A, Arnold AP, Eghbali M (2017). The Y Chromosome Plays a Protective Role in Experimental Hypoxic Pulmonary Hypertension. Am J Respir Crit Care Med. 2017 Sep 21. doi: 10.1164/rccm.201707-1345LE. [Epub ahead of print] No abstract available. PMID: 28934553

The role of sex chromosomes in the development of pulmonary hypertension has not been studied in the past. We conducted the first investigation of the role of sex chromosomes, in the absence of gonadal hormones, in the development of hypoxia-induced PH using the unique Four Core Genotypes (FCG) and XY* mouse models. We found that the Y chromosome is protective against development of hypoxia-induced pulmonary hypertension in gonadectomized mice. UCLA newsroom:

Umar S, Partow-Navid R, Ruffenach G, Iorga A, Moazeni S, Eghbali M. Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy. Biol Sex Differ. 2017 Mar 20;8:9. doi: 10.1186/s13293-017-0129-7. eCollection 2017. PMID: 28344760.

The combined role of female sex, oxidized lipids and aging in pulmonary hypertension has not been investigated before. Hence, we investigated the development of pulmonary hypertension in young and middle-aged female Apolipoprotein E-deficient mice and explored the role of estrogen replacement therapy for aging females. Our results suggested that only aging female Apolipoprotein E-deficient but not wild type mice developed severe pulmonary hypertension compared to younger females. Exogenous estrogen therapy rescued pulmonary hypertension and right ventricular hypertrophy possibly through restoration of lung estrogen receptor beta expression.

Thomas Vondriska, PhD

Kimball TH, Vondriska TM. (2020). Metabolism, Epigenetics, and Causal Inference in Heart Failure. Trends Endocrinol Metab. 2020 Mar;31(3):181-191.

Close communication between the metabolome and the epigenome sets basal susceptibility to various heart failure symptoms. This communication entrains detrimental conditions in metabolic–epigenetic memory and thus may be a target for novel treatments.

Robinson EL, Anene-Nzelu CG, Rosa-Garrido M, Foo RSY. (2020). Cardiac epigenetics: Driving signals to the cardiac epigenome in development and disease. J Mol Cell Cardiol. 2020 Nov 21;151:88.

 Readers will expand their horizons and be challenged to envision innovative strategies to further probe the epigenome and develop diagnostic and therapeutic solutions for cardiovascular pathologies.

Bertero A, Rosa-Garrido M. (2020). Three-dimensional chromatin organization in cardiac development and disease. J Mol Cell Cardiol. 2020 Nov 24;151:89-105.

This review aims to provide a comprehensive overview of our current understanding in this field, and to discuss how this knowledge can inform further research as well as clinical practice.

Mason RJ, Vondriska TM. Chromatin is the same in a relative way (but you’re older). Circ Res. 2019;125:209-211. PMID: 31268855. Epub 2019 Jul 3.

To understand how different cells arise from the same genome, it is essential to determine the structure-function relationships in chromatin, the gargantuan DNA, protein, and RNA complex that is the storage matrix evolution selected for the genetic material. Once terminal differentiation is achieved, cells need to remember what cell type they are and also to remember certain life experiences—the substrate for this epigenetic memory is chromatin. 

Karbassi E, Rosa-Garrido M, Chapski DJ, Wu Y, Ren S, Wang Y, Stefani E, Vondriska TMDirect visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling. J Mol Cell Cardiol. 2019 Mar 128:198-211. doi:10.1016/j.yjmcc.2019.02.003. Epub 2019 Feb 8.

These findings reveal locus-specific compartmentalization of stress-activated, housekeeping and silenced genes in the anatomical context of the endogenous nucleus, revealing basic principles of global chromatin structure and nuclear architecture in the regulation of gene expression in healthy and diseased conditions.

Chapski DJ, Rosa-Garrido M, Hua N, Alber F, Vondriska TM. Spatial principles of chromatin architecture associated with organ-specific gene regulation. Frontiers in Cardiovascular Medicine. 2019. 5:186doi: 10.3389/fcvm.2018.00186. Epub 2019 Jan 15.

In the present study, we sought to determine whether the structural features of the epigenome are conserved between different cell types by investigating Hi-C and RNA-seq data from heart and liver.

Kimball TH, Vondriska TM. Metabolism, epigenetics and causal inference in heart failure. Trends Endocrinol & Metab. 2019. In Press.  doi: 10.1016/j.tem.2019.11.009. Epub 2019 Dec 19.

This essay aims to challenge current thinking on metabolic-epigenetic crosstalk in heart failure, presenting hypotheses for how chronic diseases arise, take hold, and persist.

Manuel Rosa-Garrido, Douglas J. Chapski, Anthony D. Schmitt, Todd H. Kimball, Elaheh Karbassi, Emma Monte, Enrique Balderas, Matteo Pellegrini, Tsai-Ting Shih, Elizabeth Soehalim, David Liem, Peipei Ping, Niels J. Galjart, Shuxun Ren, Yibin Wang, Bing Ren, Thomas M. Vondriska. High resolution mapping of chromatin conformation in cardiac myocytes reveals structural remodeling of the epigenome in heart failure. Circulation. 2017 117.029430.

This investigation reveals chromatin architectural rearrangements that occur during heart failure and in a model in which the chromatin structural protein CTCF is depleted in the heart. Enhancer-promoter interactions, topologically associating domain boundaries, and other chromatin features are dynamic with cardiac perturbation.

Emma MonteManuel Rosa-GarridoElaheh KarbassiHaodong ChenRachel LopezChristoph D. RauJessica WangStanley F. NelsonYong WuEnrico StefaniAldons J. LusisYibin WangSiavash K. KurdistaniSarah FranklinThomas M. Vondriska. Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: Implications for Transcriptional Regulation. J Biol Chem. 2016 Jul 22; 291(30): 15428–15446. doi:  10.1074/jbc.M116.719633

This paper explores the relationship of HMGB2 and CTCF in controlling gene expression and genome organization in cardiac disease. CTCF and HMGB2 share genomic binding sites, however they do not bind together, thereby affecting chromatin structure in distinct ways.

Haodong ChenLuz OrozcoJessica WangChristoph D. RauLiudmilla RubbiShuxun Ren, Yibin WangMatteo PellegriniAldons J. LusisThomas M. Vondriska. DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated with Chromatin States. Circ Res. 2016 Mar 4; 118(5): 786–797. doi:

This study uncovers strain-specific DNA methylation patterns in healthy and failing murine hearts, to better understand epigenetic features that change with disease and to reveal epigenetic differences between distinct genetic backgrounds.

Chapski DJ, Rosa-Garrido M, Hua N, Alber F, Vondriska TM. Spatial Principles of Chromatin Architecture Associated With Organ-Specific Gene RegulationFront Cardiovasc Med. 2019 Jan 15:5:186 doi: 10.3389/fcvm.2018.00186. eCollection 2018. 

These models reveal discordant nuclear compaction strategies, with heart packaging compartment A genes preferentially toward the center of the nucleus and liver exhibiting preferential arrangement toward the periphery. Taken together, our data suggest that intra- and interchromosomal chromatin architecture plays a role in orchestrating tissue-specific gene expression.

Yibin Wang, PhD

Wang Y, Foo R, Thum T. Using "old" medications to fight new COVID-19: Re-purposing with a purpose. J Mol Cell Cardiol. 2020;146:41-42.

Luczak ED, Wu Y, Granger JM, Joiner MA, Wilson NR, Gupta A, Umapathi P, Murphy KR, Reyes Gaido OE, Sabet A, Corradini E, Tseng WW, Wang Y, Heck AJR, Wei AC, Weiss RG, Anderson ME. (2020). Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy. Nat Commun. 2020;11(1):4416.

Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase or mitochondrial-targeted CaMKII inhibition.

Cheng X, Liu YM, Li H, Zhang X, Lei F, Qin JJ, Chen Z, Deng KQ, Lin L, Chen MM, Song X, Xia M, Huang X, Liu W, Cai J, Zhang XJ, Zhou F, Zhang P, Wang Y, Ma X, Xu Q, Yang J, Ye P, Mao W, Huang X, Xia J, Zhang BH, Guo J, Zhu L, Lu Z, Yuan Y, Wei X, She ZG, Ji YX, Li H. (2020). Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020;32(4):537-47.e3.

Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.

Qin JJ, Cheng X, Zhou F, Lei F, Akolkar G, Cai J, Zhang XJ, Blet A, Xie J, Zhang P, Liu YM, Huang Z, Zhao LP, Lin L, Xia M, Chen MM, Song X, Bai L, Chen Z, Zhang X, Xiang D, Chen J, Xu Q, Ma X, Touyz RM, Gao C, Wang H, Liu L, Mao W, Luo P, Yan Y, Ye P, Chen M, Chen G, Zhu L, She ZG, Huang X, Yuan Y, Zhang BH, Wang Y, Liu PP, Li H. (2020). Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19. Hypertension. 2020;76(4):1104-12.

In conclusion, the abnormal cardiac biomarker pattern in COVID-19 patients was significantly associated with increased mortality risk, and the newly established COVID-19 prognostic cutoff values of hs-cTnI, CK-MB, (NT-pro)BNP, CK, and MYO were found to be much lower (≈50%) than reference upper normal limits for the general population.

Yokota T, McCourt J, Ma F, Ren S, Li S, Kim TH, Kurmangaliyev YZ, Nasiri R, Ahadian S, Nguyen T, Tan XHM, Zhou Y, Wu R, Rodriguez A, Cohn W, Wang Y, Whitelegge J, Ryazantsev S, Khademhosseini A, Teitell MA, Chiou PY, Birk DE, Rowat AC, Crosbie RH, Pellegrini M, Seldin M, Lusis AJ, Deb A. (2020). Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury. Cell. 2020;182(3):545-62.e23.

These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.

Zhang XJ, Qin JJ, Cheng X, Shen L, Zhao YC, Yuan Y, Lei F, Chen MM, Yang H, Bai L, Song X, Lin L, Xia M, Zhou F, Zhou J, She ZG, Zhu L, Ma X, Xu Q, Ye P, Chen G, Liu L, Mao W, Yan Y, Xiao B, Lu Z, Peng G, Liu M, Yang J, Yang L, Zhang C, Lu H, Xia X, Wang D, Liao X, Wei X, Zhang BH, Zhang X, Yang J, Zhao GN, Zhang P, Liu PP, Loomba R, Ji YX, Xia J, Wang Y, Cai J, Guo J, Li H. (2020). In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020;32(2):176-87.e4.

These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.

Yokota T, Li J, Huang J, Xiong Z, Zhang Q, Chan T, Ding Y, Rau C, Sung K, Ren S, Kulkarni R, Hsiai T, Xiao X, Touma M, Minamisawa S, Wang Y. (2020). p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart. J Clin Invest. 2020;130(10):5287-301.

In this report, we have uncovered an intrinsic cellular signaling pathway in RV-specific postnatal growth.

Cannata F, Chiarito M, Reimers B, Azzolini E, Ferrante G, My I, Viggiani G, Panico C, Regazzoli D, Ciccarelli M, Voza A, Aghemo A, Li H, Wang Y, Condorelli G, Stefanini GG. (2020). Continuation versus discontinuation of ACE inhibitors or angiotensin II receptor blockers in COVID-19: effects on blood pressure control and mortality. Eur Heart J Cardiovasc Pharmacother. 2020;6(6):412-414.

In conclusion, COVID-19 patients who continue ACEis/ARBs have a lower risk of mortality compared with those discontinuing ACEis/ARBs at the time of hospitalization or not takiing these drugs at home, suggesting that ACEis/ARBs could have a therapeutic role in COVID-19 patients.

Zhou F, Liu YM, Xie J, Li H, Lei F, Yang H, Qin JJ, Cai J, Zhang XJ, Wu B, Xia M, Xiang D, Yang C, Ma X, Xu Q, Lu Z, Lu H, Xia X, Wang D, Liao X, Peng G, Yang J, Huang X, Zhang BH, Yuan Y, Wei X, Liu PP, Wang Y, Zhang P, She ZG, Xia J, Li H. (2020). Comparative Impacts of ACE (Angiotensin-Converting Enzyme) Inhibitors Versus Angiotensin II Receptor Blockers on the Risk of COVID-19 Mortality. Hypertension. 2020;76(2):e15-e7.

In conclusion, based on the large-scale retrospective study, we demonstrated that in-hospital use of ACE inhibitors/ARBs was associated with a lower risk of 28-day death among hospitalized patients with COVID-19 and coexisting hypertension, coronary artery disease and hypertension combined with coronary artery disease.

Lu D, Chatterjee S, Xiao K, Riedel I, Wang Y, Foo R, Bär C, Thum T. (2020). MicroRNAs targeting the SARS-CoV-2 entry receptor ACE2 in cardiomyocytes. J Mol Cell Cardiol. 2020;148:46-49.

We report the first miRNA candidate that can target ACE2 in cardiomyocytes and thus may be exploited as a preventive strategy to treat cardiovascular complications of COVID-19.

Bozadjieva Kramer N, Evers SS, Shin JH, Silverwood S, Wang Y, Burant CF, Sandoval DA, Seeley RJ. (2020). The Role of Elevated Branched-Chain Amino Acids in the Effects of Vertical Sleeve Gastrectomy to Reduce Weight and Improve Glucose Regulation. Cell Rep. 2020;33(2):108239.

Our results show that a decrease in circulating BCAAs is not necessary for sustained body weight loss and improved glucose tolerance after VSG.

Liu YM, Xie J, Chen MM, Zhang X, Cheng X, Li H, Zhou F, Qin JJ, Lei F, Chen Z, Lin L, Yang C, Mao W, Chen G, Lu H, Xia X, Wang D, Liao X, Yang J, Huang X, Zhang BH, Yuan Y, Cai J, Zhang XJ, Wang Y, Zhang X, She ZG, Li H. (2020). Kidney function indicators predict adverse outcomes of COVID-19. Med (N Y). 2020 Oct 2. [Epub ahead of print].

Lin S, Neelankavil J, Wang Y. (2020). Cardioprotective Effect of Anesthetics: Translating Science to Practice. J Cardiothorac Vasc Anesth. 2020 Sep 20. [Epub ahead of print].

The present review focuses on recent clinical trials investigating the cardioprotective effects of anesthetics in the past five years. In addition to highlighting the main outcomes of these trials, the authors provide their perspectives about the current gap in the field and potential directions for future investigations.

Lusis AJ, Liu D, Wang Y. (2020). Tribute to Dr. Steve Schwartz. J Mol Cell Cardiol. 2020;147:A5-A6. Epub 2020 Apr 11..

Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D, Peng Y, Ji YX, Chen J, She ZG, Wang Y, Xu Q, Tan R, Wang H, Lin J, Luo P, Fu S, Cai H, Ye P, Xiao B, Mao W, Liu L, Yan Y, Liu M, Chen M, Zhang XJ, Wang X, Touyz RM, Xia J, Zhang BH, Huang X, Yuan Y, Rohit L, Liu PP, Li H. Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19. Circulation research. 2020. Epub 2020/04/18. doi: 10.1161/CIRCRESAHA.120.317134. Epub 2020 Jun 5.

To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.

Zhou F, Liu YM, Xie J, Li H, Lei F, Yang H, Qin JJ, Cai J, Zhang XJ, Wu B, Xia M, Xiang D, Yang C, Ma XL, Xu Q, Lu Z, Lu H, Xia X, Wang D, Liao X, Peng G, Yang J, Huang X, Zhang BH, Yuan Y, Wei X, Liu PP, Wang Y*, Zhang P, She ZG, Xia J, Li H. Comparative impacts of angiotensin converting enzyme inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality. Hypertension (Dallas, Tex : 1979). 2020. doi: 10.1161/hypertensionaha.120.15622. 2020 Jun.

Jian C, Fu J, Cheng X, Shen LJ, Ji YX, Wang X, Pan S, Tian H, Tian S, Liao R, Song K, Wang HP, Zhang X, Wang Y, Huang Z, She ZG, Zhang XJ, Zhu L, Li H. Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis. Cell metabolism. 2020;31(5):892-908.e11. Epub 2020/05/07. doi: 10.1016/j.cmet.2020.04.011. Epub 2020 May.

Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

Lusis AJ, Liu D, Wang Y. Tribute to Dr. Steve Schwartz. Journal of molecular and cellular cardiology. 2020. doi: 10.1016/j.yjmcc.2020.04.011.Epub 15 April 2020.

A tribute to Dr. Steve Schwartz.

Foo R, Wang Y, Zimmermann WH, Backs J, Wang DW. Cardiovascular molecular mechanisms of disease with COVID-19. Journal of molecular and cellular cardiology. 2020. doi: 10.1016/j.yjmcc.2020.04.010. Epub 15 April 2020.

Early clinical observations suggest that cardiovascular complications are a major cause, as well as a significant risk factor, for COVID-19 associated mortality.

Gao C, Wang Y. mRNA Metabolism in Cardiac Development and Disease: Life After Transcription. Physiol Rev. 2020;100(2):673-94. doi: 10.1152/physrev.00007.2019. Epub 20 Feb 2020.

The central dogma of molecular biology illustrates the importance of mRNAs as critical mediators between genetic information encoded at the DNA level and proteomes/metabolomes that determine the diverse functional outcome at the cellular and organ levels. Although the total number of protein-producing (coding) genes in the mammalian genome is ~20,000, it is evident that the intricate processes of cardiac development and the highly regulated physiological regulation in the normal heart, as well as the complex manifestation of pathological remodeling in a diseased heart, would require a much higher degree of complexity at the transcriptome level and beyond.

He D, Wu H, Xiang J, Ruan X, Peng P, Ruan Y, Chen YG, Wang Y, Yu Q, Zhang H, Habib SL, De Pinho RA, Liu H, Li B. Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway. Nature communications. 2020;11(1):37.  doi: 10.1038/s41467-019-13911-x. Epub 4 Jan 2020.

 Here, we show that aging-caused intestinal villus structural and functional decline is regulated by mTORC1, a sensor of nutrients and growth factors, which is highly activated in intestinal stem and progenitor cells in geriatric mice. 

Wang J, Huertas-Vazquez A, Wang Y*, Lusis AJ. Isoproterenol-Induced Cardiac Diastolic Dysfunction in Mice: A Systems Genetics Analysis. Frontiers in cardiovascular medicine. 2019;6:100. Epub 2019/08/17. doi: 10.3389/fcvm.2019.00100. 2019 Jul 31.

We examined an isoproterenol heart failure model across a panel of diverse inbred strains of mice, the Hybrid Mouse Diversity Panel (HMDP), using left atrial (LA) and lung weights as well as echocardiogram parameters as surrogates for cardiac diastolic function. 

Olver TD, Edwards JC, Jurrissen TJ, Veteto AB, Jones JL, Gao C, Rau C, Warren CM, Klutho PJ, Alex L, Ferreira-Nichols SC, Ivey JR, Thorne PK, McDonald KS, Krenz M, Baines CP, Solaro RJ, Wang Y, Ford DA, Domeier TL, Padilla J, Rector RS, Emter CA. Western Diet-Fed, Aortic-Banded Ossabaw Swine: A Preclinical Model of Cardio-Metabolic Heart Failure. JACC Basic to translational science. 2019;4(3):404-21. Epub 2019/07/18. doi: 10.1016/j.jacbts.2019.02.004. 2019 Jun 24.

This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure.

Zhou M, Jing S, Wu CY, Shu L, Dong W, Liu Y, Chen M, Wynn RM, Wang J, Gui WJ, Qi X, Lusis AJ, Li Z, Wang W, Ning G, Yang X, Chuang DT, Wang Y, Sun H. Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance. Diabetes. 2019 Jun 5. pii: db180927. doi: 10.2337/db18-0927. [Epub ahead of print]

Collectively, these data demonstrate a pivotal causal role of BCAA catabolic defect and elevated BCAAs/BCKAs in obesity-associated IR and provide proof-of-concept evidence to the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

Chen M, Gao C, Yu J, Ren S, Wang M, Wynn RM, Chuang DT, Wang Y, Sun H. Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure. Journal of the American Heart Association. 2019;8(11):e011625. Epub 2019/08/23. doi: 10.1161/JAHA.118.011625. 2019 Jun 4.

 Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.

Yu J, Zeng C, Wang Y. Epigenetics in dilated cardiomyopathy. Curr Opin Cardiol. 2019 May;34(3):260-269. doi: 10.1097/HCO.0000000000000616.

As a rapidly expanding field, epigenetic studies in DCM have the promise to yield both novel mechanistic insights as well as potential new avenues for more effective treatment of the disease.

Woo SL, Yang J, Hsu M, Yang A, Zhang L, Lee RP, Gilbuena I, Thames G, Huang J, Rasmussen A, Carpenter CL, Henning SM, Herber D, Wang Y, Li Z. Effects of branched-chain amino acids on glucose metabolism in obese, prediabetic men and women: a radnomized, crossover studyAm J Clin Nutr. 2019 Jun 1;109(6):1569-1577. doi: 10.1093/ajcn/nqz024.

Our data suggest that BCAA supplementation did not impair glucose metabolism in obese, prediabetic subjects. Further studies are needed to confirm the results seen in the present study. This study was registered at as NCT03715010.

Tzimas C, Rau CD, Buergisser PE, ean-Louis G Jr, Lee K, Chukwuneke J, Dun W, Wang Y, Tsai EJ. WIPI1 is a conserved mediator of right ventricular failure.  JCI Insight. 2019 Apr 25;5. pii: 122929. doi: 10.1172/jci.insight.122929.

These results provide the first in vivo proof-of-concept evidence that glucagon receptor antagonism is a potentially efficacious therapy to ameliorate both onset and progression of heart failure.

Hu J, Gao C, Wei C, Xue Y, Shao C, Hao Y, Gou LT, Zhou Y, Zhang J, Ren S, Chen J, Wang Y, Fu XD. RBFox1-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure. Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6172-6180. doi: 10.1073/pnas.1822176116. Epub 2019 Mar 13.

The key contribution of miR-34a to this process is further established by administrating its mimic, which is sufficient to induce cardiac defects, and by using its antagomir to alleviate RBFox2 depletion-induced heart dysfunction. These findings elucidate a potential feed-forward mechanism to account for a critical transition to cardiac decompensation and suggest a potential therapeutic avenue against heart failure.

Gao C, Ren SV, Yu J, Baal U, Thai D, Lu J, Zeng C, Yan H, Wang Y. Glucagon Receptor Antagonism Ameliorates Progression of Heart FailureJACC Basic Transl Sci. 2019 Mar 13;4(2):161-172. doi: 10.1016/j.jacbts.2018.11.001. eCollection 2019 Apr.

Our findings suggest that Wipi1 regulates mitochondrial oxidative signaling and non-canonical autophagy in cardiac myocytes. Together with our human transcriptomic analysis and corroborating studies in an RVF mouse model, these data render Wipi1 a potential target for RV-directed HF therapy.

Berry JL, Zhu W, Tang YL, Krishnamurthy P, Ge Y, Cooke JP, Chen Y, Garry DJ, Yang HT, Rajasekaran NS, Koch WJ, Li S, Domae K, Qin G, Cheng K, Kamp TJ, Ye L, Hu S, Ogle BM, Rogers JM, Abel ED, Davis ME, Prabhu SD, Liao R, Pu WT, Wang Y, Ping P, Bursac N, Vunjak-Novakovic G, Wu JC, Bolli R, Menasché P, Zhang J. Convergences of Life Sciences and Engineering in Understanding and Treating Heart FailureCirc Res. 2019 Jan 4;124(1):161-169. doi: 10.1161/CIRCRESAHA.118.314216.

Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.

Lin LY, Chun Chang S, O'Hearn J, Hui ST, Seldin M, Gupta P, Bondar G, Deng M, Jauhjainen R, Kuusisto J, Laakso M, Sinsheimer JS, Deb A, Rau C, Ren S, Wang Y, Lusis AJ, Wang JJ, Huertas-Vazquez A. Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans. G3 (Bethesda). 2018 Nov 6;8(11):3499-3506. doi: 10.1534/g3.118.200655.

Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.