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

Abstract

Carlson DL, Maass DL, White J, Sikes P, Horton JW. Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury. J Appl Physiol 103: 323-330, 2007. First published 12 April 2007 doi:10.1152/japplphysiol.01255.2006.-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 l 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 ( 23 Na/ 31 P nuclear magnetic resonance); myocardial caspase-1, -3,and -8 expression; myocyte Na ϩ (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 ϩ 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 ϩ 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 APOPTOSIS HAS BEEN IDENTIFIED as one mechanism of cardiac injury and dysfunction in several injury and disease models, including burn trauma (7,12,23,24), sepsis (19, 41), ischemic injury (14, 30, 33) and viral myocarditis (11). In the unstimulated cell, a family of intracellular cysteine proteases known as caspases exist as pro-enzymes; apoptotic stimuli such as the generation of reactive oxygen species, a rise in intracellular calcium, or inflammatory cytokine production trigger proteolytic cleavage of caspase pro-enzymes at specific aspartic acid residues, producing active enzymes (34). Caspases have been classified into two specific groups: apoptotic caspases, a large, well-characterized group that functions to accomplish programmed cell death; and inflammatory caspases, a group of proteases that regulate the inflammatory processes (2, 3, 27, 35). Caspase-1, perhaps the best-characterized caspase f...

Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart

“…Sepsis-induced myocardial dysfunction has been characterized in patients, and in vivo and in vitro animal models [3, 7, 24-27]. In the current study, septic ARVMs exhibited depressed contractile amplitude (PS) at both 1h and 18h, confirming sepsis-induced ARVM contractile dysfunction.…”

“…Carlson et al, who demonstrated that QVD-OPH prevented cardiac contractile dysfunction after major burn injury [27], support these findings. These data were also confirmed by observation in which NE produced an increased PS in both sham and septic caspase-3siRNA transfected ARVMs.…”

Treatment with gelsolin reduces brain inflammation and apoptotic signaling in mice following thermal injury

“…Because local accumulation of cytokines may induce apoptosis and significantly extend the initial injury, we also wanted to clarify whether the ability of gelsolin to down-regulate cytokine signaling could lead to decreased activation of apoptotic proteins in brain. Previous investigations have documented that severe burn injury is associated with a significant increase in apoptosis in remote organs [30,49,50] including brain [47]. A number of markers such as S100B and NSE can serve as general markers of brain injury.…”

“…It could solubilize circulating actin aggregates and shift expressed cytokines toward an anti-inflammatory profile [28], resulting in a significant reduction of mortality in endotoxemic mice. Since gelsolin has been shown to significantly blunt neutrophil recruitment to lungs [29] and to markedly attenuate vascular permeability in burn injury in rats [30], we hypothesized that, in severe burn injury of mice, a single dose of gelsolin might attenuate neuroinflammation, which might ultimately protect the brain from injurious effects following the acute insult.…”

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

“…The burn procedure was approved by the University of Texas Southwestern institutional animal care and use committee, as previously described (19). Animals were euthanized at 6h (n=3) and 48h (n=3) after burn.…”