Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury

Deborah L. Carlson, David L. Maass, Jean White, Patricia Sikes, Jureta W. Horton

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

In the heart, thermal injury activates a group of intracellular cysteine proteases known as caspases, which have been suggested to contribute to myocyte inflammation and dyshomeostasis. In this study, Sprague-Dawley rats were given either a third-degree burn over 40% total body surface area plus conventional fluid resuscitation or sham burn injury. Experimental groups included 1) sham burn given vehicle, 400 μl DMSO; 2) sham burn given Q-VD-OPh (6 mg/kg), a highly specific and stable caspase inhibitor, 24 and 1 h prior to sham burn; 3) burn given vehicle, DMSO as above; 4) burn given Q-VD-OPh (6 mg/kg) 24 and 1 h prior to burn. Twenty-four hours postburn, hearts were harvested and studied with regard to myocardial intracellular sodium concentration, intracellular pH, ATP, and phosphocreatine (23Na/31P nuclear magnetic resonance); myocardial caspase-1, -3,and -8 expression; myocyte Na (fluorescent indicator, sodium-binding benzofurzan isophthalate); myocyte secretion of TNF-α, IL-1β, IL-6, and IL-10; and myocardial performance (Langendorff). Burn injury treated with vehicle alone produced increased myocardial expression of caspase-1, -3, and -8, myocyte Na+ loading, cytokine secretion, and myocardial contractile depression; cellular pH, ATP, and phosphocreatine were stable. Q-VD-OPh treatment in burned rats attenuated myocardial caspase expression, prevented burn-related myocardial Na+ loading, attenuated myocyte cytokine responses, and improved myocardial contraction and relaxation. The present data suggest that signaling through myocardial caspases plays a pivotal role in burn-related myocyte sodium dyshomeostasis and myocyte inflammation, perhaps contributing to burn-related contractile dysfunction.

Original languageEnglish (US)
Pages (from-to)323-330
Number of pages8
JournalJournal of applied physiology
Volume103
Issue number1
DOIs
StatePublished - Jul 1 2007

Keywords

  • Inflammatory cytokines
  • Isolated cardiac myocytes
  • Langendorff
  • Myocardial inflammation
  • Nuclear magnetic resonance spectroscopy
  • Rats

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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