Atherosclerosis is a chronic inflammatory disease and is the leading cause of morbidity and death in developed countries. However, there are still fundamental gaps in our knowledge of the underlying mechanisms that contribute to its development, and end stage clinical events including plaque rupture with possible myocardial infarction or stroke. For example, although the dogma in the cardiovascular field is that an increased ratio of smooth muscle cells (SMC) to macrophages within lesions promotes plaque stability, there are major limitations in the experimental evidence for this model including major ambiguities regarding which cells within lesions are of SMC origin, the functional role of SMCs within the lesion, and the mechanisms that control transitions in SMC phenotype. Results of studies during the initial funding period of this grant provided novel evidence that oxidized phospholipids (oxPLs), which are present at high concentrations in atherosclerotic lesions and implicated in activation of endothelial cells and macrophages during atherogenesis, also induce phenotypic switching of SMC characterized by: 1) suppression of SMC marker genes;2) increased migration and proliferation;and 3) increased expression of genes implicated in plaque formation, remodeling, and/or stability. In addition, of major significance, we found that oxPL-induced phenotypic switching in cultured SMC was dependent on the embryonic stem cell (ESC) pluripotency genes KLF4 and Oct4, and mediated in part through chromatin remodeling. Studies in this proposal will test the hypothesis that phenotypic switching of SMC within atherosclerotic lesions is mediated through oxPL-induced activation of Oct4, and that this process is critical in lesion development, progression, and determination of plaque stability.
Aim 1 is to determine mechanisms by which oxPLs activate expression of the ESC pluripotency genes KLF4 and Oct4 in vascular SMC in vivo and in vitro.
Aim 1 a will test the hypothesis that oxPL-induced activation of KLF4 is dependent on cooperative interactions of NFkB and hypoxia inducible factors, and that KLF4 in turn activates Oct4 by binding to conserved KLF4 binding sites in the Oct4 promoter.
Aim 1 b will test the hypothesis that oxPL-induced activation of Oct4 in SMC is dependent on epigenetic modifications of the Oct4 and KLF4 gene loci.
Aim 2 will determine if SMC-specific conditional knockout (KO) of Oct4 alters SMC phenotypic switching and lesion development/composition in ApoE-/- Western diet fed mice. Studies will use novel SM MHC-Oct4fl/fl-YFP- ApoE-/- mice already generated in the Owens lab to simultaneously lineage trace the fate of SMC within lesions, and to determine the role of Oct4 in SMC phenotypic switching (Aim 2a), as well as effects on overall plaque size and composition (Aim 2b) including indices of plaque stability. Studies in this proposal will be the first to clearly deine which cells within lesions are derived through phenotypic modulation of SMC, what phenotypes these cells exhibit, and whether transitions in SMC phenotype are Oct4-dependent. Studies may lead to identification of novel therapeutic targets for preventing plaque rupture and myocardial infarction.

Public Health Relevance

This proposal is focused on elucidating mechanisms that contribute to development and progression of atherosclerosis, a disease which is the underlying cause of most heart attacks and stroke which are responsible for nearly half of all deaths in developed societies. Studies will test the hypothesis that products resulting from oxidation of lipids, known as oxidized phospholipids or oxPLs, induce transitions in the phenotype of vascular smooth muscle cells that are critical in the pathogenesis of this disease. Moreover studies investigate the role of a stem cell pluripotency gene known as Oct4 in this process. Studies may lead to identification of possible new therapeutic targets for stabilizing atherosclerotic plaques thereby reducing the probability of rupture leading to a heart attack or stroke.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Hasan, Ahmed AK
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University of Virginia
Schools of Medicine
United States
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