Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase

Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase

^*Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Room 6403, Charlestown, MA 02129; ^‡Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, LMRC-322, Boston, MA, 02215; and ^§Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA 02129

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 22, 1998 (received for review April 13, 1998)

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.

cerebral blood flow/cerebral ischemia

Footnotes

↵ † M.E. and U.L. contributed equally to this work.
↵ ¶ To whom reprint requests should be addressed. e-mail: Moskowitz{at}helix.mgh.harvard.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: HMG, 3-hydroxy-3-methylglutaryl; statins, HMG-CoA reductase inhibitors; CBF, cerebral blood flow; rCBF, regional CBF; NOS, NO synthase; eNOS, endothelial NOS; Sim, simvastatin; Lov, lovastatin; MCA, middle cerebral artery; TTC, triphenyltetrazolium chloride; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.