Regulation of endothelial NO production by Rho GTPase

Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (stat ins) improve endothelial function and reduce the incidence of stroke and my ocardial infarction. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins incr eased eNOS mRNA half-life but did not change eNOS gene transcription. Inhib ition of mevalonate synthesis by statins not only blocks the formation of c holesterol but also of isoprenoids. The upregulation of eNOS expression by statins was independent of cholesterol but mediated via the inhibition of t he isoprenoid geranylgeraniol, whereas farnesiol had no effect on eNOS. Imm unoblot analyses, (S-35)-GTP gamma S-binding assays and transfection studie s revealed that statins upregulate eNOS expression by blocking the geranylg eranylation of the GTPase Rho which is necessary for its membrane-associate d activity. Studies with mice showed, that statin treatment upregulates eNO S expression and function independent of serum cholesterol levels. Prophyla ctic treatment with statins augmented cerebral blood flow and reduced cereb ral infarcts in normocholesterolemic mice. These effects of statins were co mpletely absent in eNOS-deficient mice indicating the enhanced eNOS activit y by statins is the predominant mechanism by which these agents protect aga inst cerebral injury. Our results suggest that statins provide a novel prophylactic treatment str ategy for increasing blood flow and reducing brain injury during cerebral i schemia. Upregulation of eNOS by inhibiting Rho may provide a new pharmacol ogic target for the treatment of arteriosclerosis, pulmonary hypertension, and heart failure.