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

Departments of ¹Surgery and ²Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 6 November 2006 ; accepted in final form 11 April 2007

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-, IL-1, 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.

nuclear magnetic resonance spectroscopy; myocardial inflammation; inflammatory cytokines; isolated cardiac myocytes; langendorff; rats