In the previous funding period, we have shown that lipoproteins and the cholesterol lowering agent, HMG-CoA reductase inhibitors or statins, affect the vascular wall through modulation of heterotrimeric and small G-proteins in vascular endothelial cells. In this competitive renewal application, we will expand on this theme and investigate the pathophysiological effects of Rho kinases (ROCKs), the immediate downstream target of the small GTP-binding protein Rho, on endothelial function and lipoprotein-induced vascular disease. Overactivity of ROCKs is observed in cerebral and coronary vasospasm, hypertension, vascular inflammation, and arteriosclerosis. ROCKs, therefore, may be an important and still relatively unexplored therapeutic target in cardiovascular disease. Studies from our laboratory suggest that inhibition of RhoA/ROCK by statins increases eNOS expression via stabilization of eNOS mRNA and stimulates eNOS activity via activation of the phosphatidyinositol (PI)-3 kinase/protein kinase Akt pathway. The proposed studies, therefore, will extend the Pi's long-standing interest in eNOS regulation by statins and lipoproteins to investigations in the Rho/ROCK pathway. The main goal of this project is to determine whether endothelial ROCK isoforms (ROCK1 and ROCK2) contribute to endothelial dysfunction, vascular inflammation, and atherosclerosis. To achieve this, we have developed conditional ROCK1 and ROCK2 KO mice, and using the endothelial-specific Tie2.Cre mice, will attempt to target ROCK deletion to the endothelium for these studies.
Three specific aims are proposed to study these mice and their tissues.
Specific aim 1 will test the hypothesis that endothelial ROCKs are activated following non-endothelial- denuding perivascular cuff-induced injury and that endothelial deletion of ROCKs confer vascular protection.
Specific aim 2 will test the hypothesis that downstream targets of ROCKs regulate endothelial and vascular function, and contribute to some of the beneficial effects of statin therapy in ischemic stroke. The mechanism by which ROCK regulates eNOS mRNA stability will also be explored.
Specific aim 3 will test the hypothesis that endothelial ROCK deletion is protective in a mouse model of atherosclerosis. It is hoped that these studies will provide the mechanistic basis for some of the cholesterol-independent effects of statins and help establish the importance of ROCK as a novel therapeutic target for improving endothelial function and decreasing cardiovascular disease.

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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Liu, Lijuan
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Brigham and Women's Hospital
United States
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Girard, Romuald; Khanna, Omaditya; Shenkar, Robert et al. (2016) Peripheral plasma vitamin D and non-HDL cholesterol reflect the severity of cerebral cavernous malformation disease. Biomark Med 10:255-64
Tabit, Corey E; Chen, Phetcharat; Kim, Gene H et al. (2016) Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding. Circulation 134:141-52
Hofmann Bowman, Marion A; Liao, James K (2016) Relative Lack of Culprit and Obstructive Coronary Lesions in Patients With Acute Ischemic Stroke and Elevated Cardiac Troponin. Circulation 133:1228-9
Lennon, Frances E; Cianci, Gianguido C; Kanteti, Rajani et al. (2016) Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma. Sci Rep 6:24578
Kasahara, David I; Mathews, Joel A; Ninin, Fernanda M C et al. (2016) Role of ROCK2 in CD4(+) cells in allergic airways responses in mice. Clin Exp Allergy :
Kajikawa, Masato; Noma, Kensuke; Nakashima, Ayumu et al. (2015) Rho-associated kinase activity is an independent predictor of cardiovascular events in acute coronary syndrome. Hypertension 66:892-9
Knipe, Rachel S; Tager, Andrew M; Liao, James K (2015) The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev 67:103-17
Hsieh, Min-Ling; Liu, Ping-Yen; Wu, Jing-Ming et al. (2015) Interventional Transcatheter Closure Ameliorates the Leukocyte Rho Kinase Activities among Patients with Patent Ductus Arteriosus. Acta Cardiol Sin 31:494-9
Kasahara, David I; Ninin, Fernanda M C; Wurmbrand, Alison P et al. (2015) Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency. Clin Exp Allergy 45:457-70
Liao, Yi-Chu; Liu, Ping-Yen; Lin, Hsiu-Fen et al. (2015) Two functional polymorphisms of ROCK2 enhance arterial stiffening through inhibiting its activity and expression. J Mol Cell Cardiol 79:180-6

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