The Environmental Cardiology and Vascular Biology (ECVB) Laboratory focuses on studying genetic and environmental factors influential in the development of vascular inflammatory disorders such as atherosclerosis.
We are dissecting the mechanisms by which exposure to air particulate matter promotes atherosclerosis and ischemic heart disease. We have determined that inhalation of ambient ultrafine particles and motor vehicle emissions lead to systemic prooxidant and proinflammatory effects that result in the development of dysfunctional prooxidative and proinflammatory HDL, associated with enhancement of atherosclerotic lesions in hyperlipidemic mice. We are currently evaluating potential mechanisms how air pollutants exacerbate atherogenesis, such as: 1) Induction of lipid peroxidation. We are testing the hypothesis that exposure to air pollutants leads to activation of endogenous prooxidative pathways that result in oxidative alterations of plasma lipoproteins and alteration of the functional properties of circulating LDL and HDL; 2) Induction of systemic metabolic effects. We are investigating metabolic effects induced by air pollutants in systemic tissues such as the liver, resulting in alteration of carbohydrate and lipid metabolism; 3) Activation of macrophages. It appears that both alveolar and systemic macrophages could play an important role in the transduction of pulmonary effects into systemic vascular effects.
We have determined that heme oxygenase-1 (HO-1) is an important antioxidant and anti-inflammatory protective gene and together with its transcriptional regulator Nrf2, they play a central role in orchestrating the antioxidant defense of vascular cells. However, while HO-1 is an anti-atherogenic gene, Nrf2 promotes atherosclerosis instead, partly due to the regulation of genes involved in lipid metabolism and cholesterol transport. This underscores the complexity of reactive oxygen species (ROS) signaling in vascular cells. We are currently studying how tissue-specific expression of HO-1 modulates various inflammatory pathways via the use of genetic and biochemical approaches, and the importance of these pathways in vascular inflammatory disorders such as atherosclerosis, ischemia reperfusion and heart transplantation rejection response.
The use of genomic approaches has allowed us to determine that air pollutant chemicals such as those present in diesel exhaust particles are able to synergize with oxidized phospholipids generated within oxidized LDL, in the activation of proatherogenic pathways in vascular endothelial cells. We are currently conducting transcriptomic and metabolomic studies to evaluate gene-environment interactions of relevance in the induction of cardiovascular effects induced by air pollutants. These approaches should allow us to dissect pathways modulated by air pollutants in systemic tissues and identify genetic factors that could offer protection or alter individual susceptibility. We are also evaluating how HO-1 and Nrf2 expression, which exhibit significant variation among different individuals, could influence gene pathways in vascular cells and systemic tissues.
Determining vascular effects induced by air pollutants in human subjects is extremely important as it can lead to better understanding of the cardiovascular pathology and/or the identification of novel biomarkers of effects. We are conducting studies to determine whether the effects induced by air pollutants in experimental animals, consisting of enhanced systemic lipid peroxidation and HDL dysfunction, occur in human subjects as well.
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