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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052233-14
Application #
7848168
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
1995-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
14
Fiscal Year
2010
Total Cost
$402,965
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Mazurek, Stefan; Kim, Gene H (2017) Genetic and epigenetic regulation of arrhythmogenic cardiomyopathy. Biochim Biophys Acta 1863:2064-2069
Tabit, Corey E; Coplan, Mitchell J; Spencer, Kirk T et al. (2017) Cardiology Consultation in the Emergency Department Reduces Re-hospitalizations for Low-Socioeconomic Patients with Acute Decompensated Heart Failure. Am J Med 130:1112.e17-1112.e31
Kasahara, D I; Mathews, J A; Ninin, F M C et al. (2017) Role of ROCK2 in CD4+ cells in allergic airways responses in mice. Clin Exp Allergy 47:224-235
Shimizu, Toru; Narang, Nikhil; Chen, Phetcharat et al. (2017) Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction. JCI Insight 2:
Oesterle, Adam; Laufs, Ulrich; Liao, James K (2017) Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 120:229-243
Zhou, Qian; Einert, Michaela; Schmitt, Hannah et al. (2016) MnTBAP increases BMPR-II expression in endothelial cells and attenuates vascular inflammation. Vascul Pharmacol 84:67-73
Shimizu, Toru; Liao, James K (2016) Rho Kinases and Cardiac Remodeling. Circ J 80:1491-8
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

Showing the most recent 10 out of 145 publications