doi: 10.1161/01.RES.0000196564.18314.23
© 2005 American Heart Association, Inc.
Reviews |
Rho GTPases, Statins, and Nitric Oxide
From the Vascular Medicine Research Unit, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
Correspondence to James K. Liao, MD, Brigham and Women’s Hospital, 65 Landsdowne St, Rm 275, Cambridge, MA 02139. E-mail jliao{at}rics.bwh.harvard.edu
Guest Editor: This Review is part of a thematic series on The Role of Small GTPases in Cardiovascular Biology, which includes the following articles:
Rho GTPases, Statins, and Nitric Oxide
The Role of Small GTPases in Endothelial Cytoskeletal Dynamics and Sheer Stress Response
Rho Kinases in Cardiovascular Physiology and Pathophysiology
Regulation of NADPH Oxidases: the Role of Rac Proteins
Rho GTPases and Signaling by Endothelial Receptors
Anne Ridley
The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, are used in the prevention and treatment of cardiovascular diseases. Recent experimental and clinical studies suggest that statins may exert vascular protective effects beyond cholesterol reduction. For example, statins improve endothelial function by cholesterol-dependent and -independent mechanisms. The cholesterol-independent or "pleiotropic" effects of statins include the upregulation and activation of endothelial NO synthase (eNOS). Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important posttranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. Indeed, decrease in Rho GTPase responses as a consequence of statin treatment increases the production and bioavailability of endothelium-derived NO. The mechanism involves, in part, Rho/Rho-kinase (ROCK)-mediated changes in the actin cytoskeleton, which leads to decreases in eNOS mRNA stability. The regulation of eNOS by Rho GTPases, therefore, may be an important mechanism underlying the cardiovascular protective effect of statins.
Key Words: statin • Rho • Rho-kinase • endothelium • nitric oxide
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