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Post-ischemic PKC inhibition impairs myocardial calcium handling and increases contractile protein calcium

C Stamm1, I Friehs, D B Cowan

  • 1Department of Cardiac Surgery, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Cardiovascular Research
|June 12, 2001
PubMed

Insights

Protein kinase C (PKC) remains active after heart ischemia, influencing calcium handling and contractility during reperfusion. Inhibiting PKC post-ischemia hinders recovery, highlighting its protective role in myocardial function.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Physiology

Background:

  • Protein kinase C (PKC) activation impairs normal heart contractility but offers protection during myocardial ischemia.
  • It is hypothesized that PKC remains activated post-ischemia, modulating myocardial excitation-contraction coupling during early reperfusion.

Purpose of the Study:

  • To investigate the role of sustained Protein Kinase C (PKC) activation in modulating myocardial excitation-contraction coupling during early reperfusion following ischemia.
  • To assess the impact of PKC inhibition on cardiac function and calcium handling post-ischemia.

Main Methods:

  • Langendorff-perfused rabbit hearts underwent ischemia and reperfusion.
  • Total PKC activity and isoform translocation (PKC-alpha, -delta, -epsilon, -eta) were measured.
  • PKC inhibitors (chelerythrine, GF109203X) were administered during reperfusion; cardiac function, intracellular calcium, and myofilament responsiveness were assessed.

Main Results:

  • Total PKC activity increased post-ischemia, with PKC-epsilon identified as the main active isoform during reperfusion.
  • PKC inhibition primarily impaired diastolic relaxation and increased myofilament calcium sensitivity.
  • Post-ischemic hearts showed delayed diastolic calcium removal and exacerbated intracellular calcium overload, with depressed systolic function linked to lower calcium transient amplitude.

Conclusions:

  • PKC is activated during ischemia and remains active in early reperfusion, playing a crucial role in cardiac recovery.
  • Inhibiting post-ischemic PKC activity impairs functional recovery by disrupting calcium homeostasis and increasing contractile protein calcium sensitivity, leading to poor diastolic relaxation.
  • Post-ischemic PKC activation may be a protective mechanism to restore calcium balance and attenuate contractile sensitivity during reperfusion calcium overload.
Abstract

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