title: HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size.
abstract: Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors protect the vasculature from inflammation and atherosclerosis by cholesterol dependent and cholesterol independent mechanisms. We hypothesized that HMG-CoA reductase inhibitors decrease exocytosis of Weibel-Palade bodies, endothelial cell granules whose contents promote thrombosis and vascular inflammation. We pretreated human aortic endothelial cells with simvastatin for 24 hours, then stimulated the cells with thrombin, and measured the amount of vWF released into the media. We then measured the effect of simvastatin on myocardial infarction in mice. Simvastatin decreased thrombin-stimulated Weibel-Palade body exocytosis by 89%. Simvastatin inhibited exocytosis in part by increasing synthesis of nitric oxide (NO), which S-nitrosylated N-ethylmaleimide sensitive factor (NSF), a critical regulator of exocytosis. Simvastatin treatment attenuated myocardial infarct size by 58% in wild-type but not eNOS knockout mice. Furthermore, simvastatin decreased endothelial exocytosis and neutrophil infiltration into ischemic-reperfused myocardium, which was mediated in part by P-selectin contained in Weibel-Palade bodies. However, simvastatin did not affect exocytosis and inflammation in myocardial infarcts of eNOS knockout mice. Inhibition of endothelial exocytosis is a novel mechanism by which HMG-CoA reductase inhibitors may reduce vascular inflammation, inhibit thrombosis, and protect the ischemic myocardium. These findings may explain part of the pleiotropic effects of statin therapy for patients with cardiovascular disease.
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Munekazu
authors.initials: M
authors.lastname: Yamakuchi
authors.forename: James J M
authors.initials: JJ
authors.lastname: Greer
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cameron
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsushita
authors.forename: Craig N
authors.initials: CN
authors.lastname: Morrell
authors.forename: Karen
authors.initials: K
authors.lastname: Talbot-Fox
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lowenstein
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D052066:N-Ethylmaleimide-Sensitive Proteins; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019821:Simvastatin / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000187:drug effects
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D033921:Vesicular Transport Proteins; D009569:Nitric Oxide; D019821:Simvastatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D052066:N-Ethylmaleimide-Sensitive Proteins; C498733:Nsf protein, mouse