The Eghbali Laboratory's work focuses on the molecular basis of the remodeling of voltage-activated K+ channels in the heart by sex hormones. Dr. Eghbali and her colleagues have identified a key molecule that controls the production of oxidized lipids, and is reduced in the lungs and blood of patients with pulmonary hypertension; this discovery could lead to the development of a new blood test to aid in early detection. Pulmonary hypertension is up to four times more common in women, and Dr. Eghbali's team is leading in the investigation, for the first time, of the role of sex chromosomes in the development of this devastating disease. The Y chromosome appears to be protective, and the team's goal is to identify the gene(s) on the Y chromosome responsible for the protective effect. This research may ultimately explain the prevalence of pulmonary hypertension among women and potentially elucidate a novel therapeutic approach to treatment. In addition, researchers in the Eghbali Laboratory have developed the first model of combined pulmonary fibrosis and pulmonary hypertension in rats, effectively simulating the human disease. They are focusing specifically on the study of a molecule called microRNA 125b-3p. This molecule may serve as a biomarker for disease progression, and may also serve as a therapeutic target for treatment.
Dr. Eghbali is our department’s Director of Physician-Scientist Training, and Director of the Basic Science Training Environment. She received her PhD degree from the John Curtin School of Medical Research, Australian National University.
Iorga A, Umar S, Ruffenach G, Aryan L, Li J, Sharma S, Motayagheni N, Nadadur RD, Bopassa JC, Eghbali M. Estrogen Rescues Heart Failure Through Estrogen Receptor Beta Activation. Biol Sex Differ; October 2018 9(1):48. doi: 10.1186/s13293-018-0206-6. PMID: 30376877. https://www.ncbi.nlm.nih.gov/pubmed/30376877
We have previously shown that estrogen treatment rescues heart failure in mice. In this paper we show the rescue action of estrogen is mainly mediated through estrogen receptor beta.
Touma M., Kang X., Gao F., Zhao Y., Cass A.A., Biniwale R., Xiao X., Eghbali M., Coppola G., Reemtsen B., & Wang Y. (2017). Wnt11 Regulates Cardiac Chamber Development and Disease During Perinatal Maturation. JCI Insight. 2017 September. 2(17). pii: 94904. doi: 10.1172/jci.insight.94904. PMC5621892. https://www.ncbi.nlm.nih.gov/pubmed/28878122
Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. In this paper systems genomic and functional biology analyses of the perinatal chamber specific transcriptome, we identified Wnt11 as a prominent regulator of chamber-specific proliferation. We also show downregulation of Wnt11 expression was associated with cyanotic congenital heart defect phenotypes and correlated with O2 saturation levels in hypoxemic infants. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and downregulation of Wnt11 in hypoxemic infantile hearts was associated with Rb1 suppression and induction of proliferation markers. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.
Vaillancourt M., Chia P., Sarji S., Nguyen J., Hoftman N., Ruffenach G., Eghbali M., Mahajan A. & Umar S. (2017). Autonomic Nervous System Involvement in Pulmonary Arterial Hypertension. Respir Res. 2017 December. 18(1):201. doi: 10.1186/s12931-017-0679-6. PMCID: PMC5715548. https://www.ncbi.nlm.nih.gov/pubmed/29202826
Autonomic nervous system involvement in the pathogenesis of pulmonary arterial hypertension has been demonstrated several years ago, however the extent of this involvement is not fully understood. This review summarizes the multiple aspects of autonomic nervous system involvement in pulmonary arterial hypertension and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of pulmonary arterial hypertension.
Iorga A., Cunningham C.M., Moazeni S, Ruffench G, Umar S. & Eghbali M. (2017). The Protective Role of Estrogen and Estrogen Receptors in Cardiovascular Disease and the Controversial Use of Estrogen Therapy. Biol Sex Differ 2017 October. 8(1):33. doi: 10.1186/s13293-017-0152-8. PMID: 29065927. https://www.ncbi.nlm.nih.gov/pubmed/29065927
This review summarizes the protective role of estrogen and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. The controversies surrounding the clinical use of exogenous estrogen as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed.
Li J, Ruffenach G, Kararigas G, Cunningham CM, Motayagheni N, Barakai N, Umar S, Regitz-Zagrosek V, Eghbali M. Intralipid Protects the Heart in Late Pregnancy Against Ischemia/reperfusion Injury via Caveolin2/STAT3/GSK-3β Pathway. J Mol Cell Cardiol. Jan. 2017 – Vol 102, p. 108-116. https://doi.org/10.1016/j.yjmcc.2016.11.006
The heart of a rodent in late pregnancy is more prone to ischemia/reperfusion injury compared to that of a non-pregnant rodent. Intralipid, an emulsion of fatty acids, protects the heart in late pregnancy against ischemia/reperfusion injury by inhibiting the mPTP opening through the Cav2/STAT3/GSK-3β pathway.
Arnold A.P, Cassis L.A., Eghbali M., Reue K. & Sandberg K. (2017). Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:746-756. https://doi.org/10.1161/ATVBAHA.116.307301
This review summarizes recent evidence concerning hormonal and sex chromosome effects in obesity, atherosclerosis, aneurysms, ischemia/reperfusion injury, and hypertension. Cardiovascular diseases occur and progress differently between sexes due to sex-specific protective and harmful effects. Gonadal hormones, especially estrogens and androgens, have long been found to account for some sex differences in cardiovascular diseases, and molecular mechanisms mediating these effects have recently been elucidated. More recently, the effects of sex chromosome genes have also been implicated as contributors in animal models of cardiovascular diseases, especially a deleterious effect of the second X chromosome found in females but not in males.
Vaidya B., Pangallo M., Ruffenach G., Cunningham C.M., Perron J.C., Kolluru S., Eghbali M., Gupta V. (2017). Advances in Treatment of Pulmonary Arterial Hypertension: Patent Review. Expert Opin Ther Pat. 2017 Aug;27(8):907-918. http://dx.doi.org/10.1080/13543776.2017.1313232
Pulmonary arterial hypertension (PAH) has recently been considered as a cancer-like disease with over-proliferation of pulmonary arterial smooth muscle cells and dysfunction of endothelial cells. New cellular and molecular biological advances have revealed novel target/pathways involved in the pathogenesis and progression of PAH. This review highlights recently filed patents describing novel agents acting on investigational targets as well as novel compounds with improved characteristics acting on established targets. Patents describing combinations of conventional and investigational compounds are also discussed.
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. https://www.ncbi.nlm.nih.gov/pubmed/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.
Sharma S, Ruffenach G, Umar S, Motayagheni N, Reddy ST, Eghbali M. Role of Oxidized Lipids in Pulmonary Arterial Hypertension. Pulm Circ. 2016 Sep;6(3):261-73. doi: 10.1086/687293. Review. PMID: 27683603. https://www.ncbi.nlm.nih.gov/pubmed/27683603
We focused on the current understanding of the role of oxidized lipids, lipid metabolism, peroxidation, and oxidative stress in the progression of pulmonary hypertension. This review also discussed the relevance of apolipoprotein A-I mimetic peptides and microRNA-193, which are known to regulate the levels of oxidized lipids, as potential therapeutics in pulmonary hypertension.
Anwar A, Ruffenach G, Mahajan A, Eghbali M, Umar S. Novel Biomarkers for Pulmonary Arterial Hypertension. Respir Res. 2016 Jul 20;17(1):88. doi: 10.1186/s12931-016-0396-6. Review. PMID: 27439993. https://www.ncbi.nlm.nih.gov/pubmed/27439993
A simple non-invasive test to frequently monitor the patients with pulmonary hypertension is much needed. Search for a novel biomarker for pulmonary hypertension that can be detected by a simple test is ongoing and many different options are being studied. Here we reviewed some of the new and unique pre-clinical options for potential pulmonary hypertension biomarkers. A biomarker that can be detected in blood, urine or breath condensate and correlates with disease severity, progression and response to therapy may result in significant cost reduction and improved patient outcomes.
Arnold AP, Reue K, Eghbali M, Vilain E, Chen X, Ghahramani N, Itoh Y, Li J, Link JC, Ngun T, & Shayna Williams-Burris.The Importance of Having Two X Chromosomes. Philos Trans R Soc Lond B Biol Sci. 2016 February 371(1688):20150113. doi: 10.1098/rstb.2015.0113.PMCID:4785899.https://www.ncbi.nlm.nih.gov/pubmed/26833834
Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models with the same type of gonad but with one versus two copies of the X chromosome demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes. The review summarizes the studies demonstrating number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischemia/reperfusion injury and behaviour.
Iorga A, Li J, Sharma S, Umar S, Bopassa JC, Nadadur RD, Centala A, Ren S, Saito T, Toro L, Wang Y, Stefani E, Eghbali M. Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy. J Am Heart Assoc. 2016 Jan 22;5(1). pii: e002482. doi: 10.1161/JAHA.115.002482. PMID: 26802104. https://www.ncbi.nlm.nih.gov/pubmed/26802104
Estrogen pre-treatment has been shown to attenuate the development of heart hypertrophy, but it was not known whether estrogen could also rescue heart failure. We discovered that estrogen rescues pre-existing heart failure in mice by restoring cardiac estrogen and aromatase levels, stimulating cardiac angiogenesis, and by suppressing myocardial fibrosis.