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Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.

  • Author(s): Gardner, RT;
  • Wang, L;
  • Lang, BT;
  • Cregg, JM;
  • Dunbar, CL;
  • Woodward, WR;
  • Silver, J;
  • Ripplinger, CM;
  • Habecker, BA
  • et al.
Abstract

Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.

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