Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury
Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury
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DOI：
10.1152/japplphysiol.01255.2006
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发表时间：
2007-07-01
影响因子：
3.3
通讯作者：
Horton, Jureta W.
中科院分区：
文献类型：
--
作者：
Carlson, Deborah L.;Maass, David L.;Horton, Jureta W.
在心脏中，热损伤会激活一组被称为半胱氨酸酶的细胞内半胱氨酸蛋白酶。它们被认为与心肌细胞炎症和动态平衡失调有关。在这项研究中，Spraogue-Dawley大鼠被给予超过全身40%的三度烧伤：；表面积加常规液体复苏或假烧伤。试验组包括：1)假烧伤模型组，400亩L二甲基亚砜；2)假烧伤模型组，烧伤前24、1h给予高特异性、高稳定性的半胱氨酸酶抑制剂Q-VD-Oph(6 mg/kg)；3)烧伤模型组，DMSO如上；(4)烧伤前24、1h给予Q-VD-Oph 16 mg/kg。伤后24小时取心，测定心肌细胞内钠离子浓度、细胞内pH、三磷酸腺苷、磷酸肌酸(Na-23/P-31核磁共振)和半胱氨酸天冬氨酸氨基转移酶-1(caspase-1)。-3和-8表达；心肌细胞Na+(荧光指示剂，钠结合型间苯二甲酸苯并呋喃)；心肌细胞分泌肿瘤坏死因子-α、白介素1β、白介素6和白介素10；以及心肌功能(朗宁多夫)。单纯赋形剂治疗后，心肌caspase-1、-3、-8表达增加，心肌细胞Na+负荷量增加，细胞因子分泌增加，心肌收缩抑制：细胞pH降低。三磷酸腺苷、磷酸肌酸稳定。Q-VD-Oph治疗可降低烧伤大鼠心肌caspase的表达。预防烧伤相关心肌Na+负荷，减轻心肌细胞细胞因子反应，改善心肌收缩和松弛。目前的数据表明，通过心肌caspase的信号在烧伤相关的心肌细胞钠平衡失调和心肌细胞炎症中起着关键作用，可能是导致烧伤相关收缩功能障碍的原因之一。
In the heart, thermal injury activates a group of intracellular cysteine proteases known as 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 mu l DMSO: 2) sham burn given Q-VD-OPh (6 mg/kg), a highly specific and stable caspase inhibitor, 24 and I h prior to sham burn; 3) burn given vehicle, DMSO as above; 4) burn given Q-VD-OPh 16 mg/kg) 24 and I 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 (Na-23/P-31 nuclear magnetic resonance); myocardial caspase-1. -3, and -8 expression; myocyte Na+ (fluorescent indicator, sodium-binding benzofurzan isophthalate); myocyte secretion of TNF-alpha, IL-1 beta, 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, attennated 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.