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Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia

Ching-Hui Weng1, Fa-Po Chung1,2, Yao-Chang Chen3

  • 1Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Scientific Reports
|December 15, 2016
PubMed

Insights

Matrix metalloproteinase-9 (MMP-9) plays a causal role in ventricular arrhythmia by disrupting calcium homeostasis. Inhibiting MMP-9 protects against arrhythmia by stabilizing calcium levels and reducing leakage.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Biochemistry

Background:

  • Observational studies link matrix metalloproteinase-9 (MMP-9) to ventricular arrhythmia.
  • The precise causal role and underlying mechanisms of MMP-9 in ventricular arrhythmia remain unclear.

Purpose of the Study:

  • To investigate the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia.
  • To determine if MMP-9 deficiency or inhibition can prevent ventricular arrhythmia.

Main Methods:

  • Utilized MMP-9-deficient mice and angiotensin II (Ang II) treatment to induce arrhythmia.
  • Examined protein kinase A (PKA) and ryanodine receptor phosphorylation (pS2808) levels.
  • Analyzed calcium dynamics in isolated cardiomyocytes using confocal imaging.
  • Investigated effects in human induced pluripotent stem cell-derived cardiomyocytes.

Main Results:

  • MMP-9 deficiency protected mice from Ang II-induced ventricular arrhythmia.
  • Increased PKA and pS2808 correlated with ventricular arrhythmia, and MMP-9 deficiency prevented these increases.
  • MMP-9 inhibition in cardiomyocytes prevented calcium leakage and reduced irregular calcium transients.
  • MMP-9 inhibition also prevented abnormal calcium leakage in human iPSC-derived cardiomyocytes.

Conclusions:

  • Myocardial MMP-9 is causally involved in ventricular arrhythmia.
  • MMP-9 inhibition prevents ventricular arrhythmia by modulating calcium homeostasis and reducing sarcoplasmic reticulum calcium leakage.
  • Targeting MMP-9 offers a potential therapeutic strategy for ventricular arrhythmia.

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