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Related Experiment Videos

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.

Circulation Research
|May 21, 2005
PubMed
Summary
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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.

Related Experiment Videos

  • 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.