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Published on: November 10, 2017
HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size
Munekazu Yamakuchi1, James J M Greer, Scott J Cameron
1Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Insights
Statins, like simvastatin, reduce vascular inflammation and thrombosis by inhibiting endothelial cell exocytosis. This mechanism, involving nitric oxide and protecting against myocardial infarction, explains some of their cardiovascular benefits.
Area of Science:
- Cardiovascular Science
- Endothelial Biology
- Pharmacology
Background:
- HMG-CoA reductase inhibitors (statins) offer vascular protection via cholesterol-dependent and independent pathways.
- Weibel-Palade bodies (WPBs) are endothelial cell granules releasing pro-thrombotic and pro-inflammatory factors.
- Statins may inhibit WPB exocytosis, a novel mechanism for their pleiotropic effects.
Purpose of the Study:
- To investigate if statins, specifically simvastatin, reduce WPB exocytosis.
- To elucidate the molecular mechanisms underlying simvastatin's effect on endothelial exocytosis.
- To determine the in vivo relevance of simvastatin-induced inhibition of endothelial exocytosis in myocardial infarction.
Main Methods:
- Human aortic endothelial cells were pretreated with simvastatin and stimulated with thrombin to measure von Willebrand factor (vWF) release.
- Nitric oxide (NO) synthesis and S-nitrosylation of N-ethylmaleimide sensitive factor (NSF) were assessed.
- The effect of simvastatin on myocardial infarct size and neutrophil infiltration was evaluated in wild-type and eNOS knockout mice.
Main Results:
- Simvastatin significantly reduced thrombin-stimulated WPB exocytosis by 89%.
- Simvastatin increased NO synthesis, leading to S-nitrosylation of NSF, which inhibited exocytosis.
- Simvastatin attenuated myocardial infarct size by 58% in wild-type mice but not in eNOS knockout mice, also reducing neutrophil infiltration.
Conclusions:
- Inhibition of endothelial WPB exocytosis is a novel mechanism for statin-mediated vascular protection.
- This mechanism involves NO-dependent S-nitrosylation of NSF.
- Statins may reduce vascular inflammation, inhibit thrombosis, and protect ischemic myocardium through this pathway, contributing to their pleiotropic effects in cardiovascular disease.
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.
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