STROKE PROTECTION BY 3-HYDROXY-3-METHYLGLUTARYL (HMG)-COA REDUCTASE INHIBITORS MEDIATED BY ENDOTHELIAL NITRIC-OXIDE SYNTHASE

The treatment of ischemic strokes is limited to prophylactic agents th at block the coagulation cascade. Here, we show that cholesterol-lower ing agents, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, protect against cerebral injury by a previously unidentified mechanis m involving the selective up-regulation of endothelial NO synthase (eN OS). Prophylactic treatment with HMG-CoA reductase inhibitors augments cerebral blood flow, reduces cerebral infarct size, and improves neur ological function in normocholesterolemic mice. The up-regulation of e NOS by HMG-CoA reductase inhibitors is not associated with changes in serum cholesterol levels, but is reversed by cotreatment with L-mevalo nate and by the downstream isoprenoid, geranylgeranyl pyrophosphate an d not by.farnesyl pyrophosphate. The blood flow and neuroprotective ef fects of HMG-CoA reductase inhibitors are completely absent in eNOS-de ficient mice, indicating that enhanced eNOS activity by HMG-CoA reduct ase inhibitors is the predominant if not the only mechanism by which t hese agents protect against cerebral injury. Our results suggest that HMG-CoA reductase inhibitors provide a prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral i schemia.