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Inhibition of matrix metalloproteinases prevents peroxynitrite-induced contractile dysfunction in the isolated

H León1, I Baczkó, G Sawicki

  • 1Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada.

British Journal of Pharmacology
|December 12, 2007
PubMed
Abstract

Insights

Peroxynitrite (ONOO(-)) impairs heart cell function by activating matrix metalloproteinase-2 (MMP-2). Inhibiting MMPs protects cardiac myocytes from ONOO(-)-induced contractile failure, independent of matrix protein breakdown.

Area of Science:

  • Cardiovascular Physiology
  • Oxidative Stress Biology
  • Enzymology

Background:

  • The potent oxidant peroxynitrite (ONOO(-)) contributes to cardiac mechanical dysfunction.
  • Matrix metalloproteinase-2 (MMP-2) activation is implicated in ONOO(-)-induced cardiac impairment.
  • The role of MMPs in ONOO(-)-induced contractile dysfunction, independent of extracellular matrix proteolysis, requires elucidation.

Purpose of the Study:

  • To investigate the direct effects of ONOO(-) on contractile function in isolated cardiac myocytes.
  • To determine if MMPs mediate ONOO(-)-induced alterations in myocyte contractility.
  • To explore the mechanism by which MMP inhibition confers protection against ONOO(-).

Main Methods:

  • Ventricular myocytes were isolated from adult rats and subjected to varying concentrations of ONOO(-).
  • Contractile function was assessed by measuring contraction cease time (CCT) using a video edge-detector.
  • Intracellular calcium dynamics and MMP-2 activity were analyzed, with and without MMP inhibitors (doxycycline, PD 166793).

Main Results:

  • ONOO(-) induced a concentration-dependent decrease in CCT, indicating impaired contractility.
  • MMP-2 activity was elevated in myocytes exposed to ONOO(-).
  • MMP inhibitors significantly attenuated the ONOO(-)-induced decline in CCT and normalized calcium handling.

Conclusions:

  • This study demonstrates that MMPs play a critical role in ONOO(-)-induced cardiac myocyte contractile failure.
  • Inhibition of MMPs protects cardiac myocytes from ONOO(-)-induced dysfunction.
  • The protective effect of MMP inhibition is independent of MMPs' proteolytic activity on extracellular matrix proteins.

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