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Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes

Huei-Ping Tzeng1, Jinping Fan, Jesus G Vallejo

  • 1Department of medicine, Winters Center for Heart Failure Research, Houston, TX 77030, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|January 29, 2008
PubMed

Insights

High-mobility group box 1 (HMGB1) significantly impairs heart cell contraction and calcium handling. This suggests HMGB1 may act as a novel myocardial depressant factor in cardiac injury.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cellular Physiology

Background:

  • High-mobility group box 1 (HMGB1) is a late inflammatory mediator implicated in sepsis-induced cardiovascular collapse.
  • The specific effects of HMGB1 on cardiac myocytes remained largely unknown.

Purpose of the Study:

  • To investigate the direct effects of HMGB1 on the function of isolated feline cardiac myocytes.
  • To elucidate the mechanisms underlying HMGB1's impact on cardiac contractility and calcium homeostasis.

Main Methods:

  • Isolated feline cardiac myocytes were treated with HMGB1.
  • Sarcomere shortening was measured to assess contractility.
  • Intracellular calcium transients were monitored using fluo-3.
  • L-type calcium currents were analyzed via patch-clamp electrophysiology.
  • PKC-epsilon translocation and the effects of a PKC inhibitor were examined.

Main Results:

  • HMGB1 treatment caused a significant decrease in sarcomere shortening (70%) and peak intracellular calcium transients (50%).
  • These negative inotropic effects were partially reversible upon HMGB1 washout.
  • Patch-clamp analysis revealed significant inhibition of inward L-type calcium currents.
  • HMGB1 induced PKC-epsilon translocation, and a PKC inhibitor partially reversed the negative inotropic effects.

Conclusions:

  • HMGB1 directly impairs cardiac myocyte contractility by reducing calcium availability.
  • HMGB1 modulates membrane calcium influx, contributing to myocardial depression.
  • HMGB1 may function as a novel myocardial depressant factor during cardiac injury.

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