Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload
Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload
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DOI：
10.1016/j.yjmcc.2007.10.010
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发表时间：
2008-01-01
影响因子：
5
通讯作者：
Ahmad, Hasan
中科院分区：
文献类型：
--
作者：
Greyson, Clifford R.;Schwartz, Gregory G.;Ahmad, Hasan
急性右心室压力过载引起的右心室收缩衰竭是发病率和死亡率的重要原因，但这种情况下右心室收缩衰竭的机制尚不完全明确。我们假设急性右心室压力过载引起的右心室功能障碍部分是由于钙蛋白酶的激活，因此钙蛋白酶抑制可以减轻右心室功能障碍。在麻醉状态下，开胸猪用钙蛋白酶抑制剂MDL-28170或无活性载药处理，然后进行急性右心室压力过载90分钟。采用区域Frank-Starling关系评价右心室收缩功能。分析右心室心肌组织钙蛋白酶激活和钙蛋白酶介导的蛋白水解的证据。右心室压力过载导致严重的收缩功能障碍，并伴有内源性钙蛋白酶抑制剂钙pastatin的显著改变，这是钙蛋白酶激活的典型特征。MDL-28170减弱RV游离壁功能障碍50%以上。然而，假手术猪和急性右心室压力过载猪之间，或载药猪和MDL-28170处理猪之间，在spectrin、desmin、肌钙蛋白- i或SERCA2的降解方面没有差异。急性右心室压力过载引起钙蛋白酶激活，钙蛋白酶抑制剂MDL-28170可减轻急性右心室压力过载引起的右心室收缩功能障碍；然而，这种效果不能通过抑制钙蛋白酶介导的spectrin、desmin、troponin-I或SERCA2的降解来解释。由于这是首次报道任何药物可以直接减轻急性右心室压力过载时右心室收缩功能障碍，因此有必要进一步研究MDL-28170在这种情况下的作用机制。(C) 2007爱思唯尔公司版权所有。
Right ventricular contractile failure from acute RV pressure overload is an important cause of morbidity and mortality, but the mechanism of RV failure in this setting is incompletely defined. We hypothesized that RV dysfunction from acute RV pressure overload is, in part, due to activation of calpain, and that calpain inhibition would therefore attenuate RV dysfunction. Anesthetized, open chest pigs were treated with the calpain inhibitor MDL-28170 or with inactive vehicle, and then subjected to acute RV pressure overload for 90 min. RV contractile function was assessed by the regional Frank-Starling relation. RV myocardial tissue was analyzed for evidence of calpain activation and calpain-mediated proteolysis. RV pressure overload caused severe contractile dysfunction, along with significant alterations in the endogenous calpain inhibitor calpastatin typical of calpain activation. MDL-28170 attenuated RV free wall dysfunction by more than 50%. However, there were no differences in degradation of spectrin, desmin, troponin-I or SERCA2 between SHAM operated pigs and pigs subjected to acute RV pressure overload, or between vehicle and MDL-28170 treated pigs. Acute RV pressure overload causes calpain activation, and RV contractile dysfunction from acute RV pressure overload is attenuated by the calpain inhibitor MDL-28170; however, the effect is not explained by inhibition of calpain-mediated degradation of spectrin, desmin, troponin-I or SERCA2. Because this is the first report of any agent that can directly attenuate RV contractile dysfunction in acute RV pressure overload, further investigation of the mechanism of action of MDL-28170 in this setting is warranted. (C) 2007 Elsevier Inc. All rights reserved.