Authors
Endres M. Laufs U. Huang Z. Nakamura T. Huang P. Moskowitz MA. Liao JK.
Institution
Stroke and Neurovascular Regulation Laboratory,
Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Room
6403, Charlestown, MA 02129, USA.
Title
Stroke protection by
3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by
endothelial nitric oxide synthase.
Source
Proceedings of the National Academy of Sciences of the United States of
America. 95(15):8880-5, 1998 Jul 21.
Abstract
The treatment of ischemic strokes is limited to prophylactic
agents that block the coagulation cascade. Here, we show that
cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase
inhibitors, protect against cerebral injury by a previously unidentified
mechanism involving the selective up-regulation of endothelial NO synthase
(eNOS). Prophylactic treatment with HMG-CoA reductase inhibitors augments
cerebral blood flow, reduces cerebral infarct size, and improves neurological
function in normocholesterolemic mice. The up-regulation of eNOS by HMG-CoA
reductase inhibitors is not associated with changes in serum cholesterol
levels, but is reversed by cotreatment with L-mevalonate and by the
downstream isoprenoid, geranylgeranyl pyrophosphate and not by farnesyl
pyrophosphate. The blood flow and neuroprotective effects of HMG-CoA
reductase inhibitors are completely absent in eNOS-deficient mice, indicating
that enhanced eNOS activity by HMG-CoA reductase inhibitors is the
predominant if not the only mechanism by which these 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 ischemia.