Invited Symposium: On/Off Switches for Nitric Oxide Synthases
Endres, M (Massachusetts General Hospital, Boston, USA)
Moskowitz, MA (Massachusetts General Hospital, Boston, USA)
Liao, JK (Brigham and Women's Hospital, Boston, USA)
Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (statins) improve endothelial function. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins increased eNOS mRNA half-life but did not change eNOS gene transcription. Inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol but also of isoprenoids. The upregulation of eNOS expression by statins was mediated via the inhibition of geranylgeraniol, but not farnesiol. Immunoblot analyses, [35S]-GTPgS-binding assays and transfection studies revealed that statins upregulate eNOS expression by blocking the geranylgeranylation of the GTPase Rho which is necessary for its membrane-associated activity. Studies with mice showed, that statin treatment upregulates eNOS expression and function independent of serum cholesterol levels. Prophylactic treatment with statins augmented cerebral blood flow and reduced cerebral infarcts in normocholesterolemic mice. These effects of statins were completely absent in eNOS-deficient mice indicating that enhanced eNOS activity by statins is the predominant mechanism by which these agents protect against cerebral injury. Our results suggest that statins provide a novel prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia.
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|Laufs, U; Endres, M; Moskowitz, MA; Liao, JK; (1998). Regulation of Endothelial Nitric Oxide Synthase Production by Inhibition of HMG-CoA Reductase. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/garcia-cardena/laufs0888/index.html|
|© 1998 Author(s) Hold Copyright|