Atherosclerosis is the major cause of death and disability in the United States. Endothelial dysfunction and inflammation are hallmarks of atherosclerosis. The risk factors such as hypertension, obesity, diabetes, smoking, hyperlipidemia, and genetic predisposition create a proinflammatory environment that leads to endothelial dysfunction and atherogenesis. The lesions of atherosclerosis have a non-uniform distribution in the human vasculature. Straight regions of arteries are exposed to steady laminar blood flow and are protected from atherosclerosis, whereas regions containing bifurcations and curvatures are characterized by disturbed blood flow that predisposes vessels to atherosclerotic lesion formation. The overall goals of this project are to elucidate the nature of laminar flow atheroprotection, identify the key molecules and signal pathways in the anti-atherogenic programs of physiological laminar flow. We will further define new strategies to activate the atheroprotective mechanism in the atheroprone regions of arteries exposed to disturbed flow to prevent atherosclerosis. The transcription factor Kr?ppel-like factor 2 (KLF2) has emerged as a key atheroprotective gene integrating multiple endothelial functions. In particular, KLF2 is a laminar flow responsive gene and mediates many atheroprotective effects of laminar flow including the inhibition of leukocyte adhesion to endothelium and the improvement of endothelial dysfunction through enhancing endothelial nitric oxide synthase (eNOS) expression and activity. However, the molecular mechanisms connecting laminar flow to KLF2 activation and physiological function in endothelial biology remain largely elusive. New evidence emerging from our laboratory suggests that histone deacetylase 5 (HDAC5) is a crucial molecular linker facilitating L-flow activation of KLF2 in the atheroprotective processes. To test our hypothesis, we will use a combination of biochemical, cell biological and genetic approaches in cultured cells and mice to examine the functional role of HDAC5 and molecular mechanisms in laminar flow regulation of KLF2 and atheroprotection. The results of this project will provide a detailed understanding of the mechanisms involved in laminar flow atheroprotection and will have implications for the development of new therapeutic approaches, such as specifically removing HDAC5 repression on KLF2, to limit atherosclerosis.

Public Health Relevance

Atherosclerosis is the major cause of death and disability in the United States. The lesions of atherosclerosis show a focal pattern of distribution in the human vasculature, and steady laminar blood flow within large straight arteries provides an atheroprotective function mainly through upregulation of the atheroprotective genes in endothelial cells. We have recently found that HDAC5, an important transcriptional repressor, is involved in laminar flow-mediated regulation of the atheroprotective genes. This proposed study will investigate mechanical and molecular mechanisms derived from laminar flow on HDAC5, and develop novel approaches to inhibit HDAC5, establishing exogenous atheroprotection in traditionally artheroprone vasculature. The proposal will significantly increase our understanding of mechanisms by which laminar flow mediates atheroprotection, and therefore provide the basis to develop new therapies to prevent atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Fleg, Jerome
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University of Rochester
Internal Medicine/Medicine
School of Medicine & Dentistry
United States
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