Calpain Activation and Inhibition in Right Heart Failure

描述（由申请人提供）：急性压力过载引起的右心衰是肺栓塞、缺氧性肺血管收缩、体外循环和心脏移植后发病和死亡的主要原因。以前认为，急性压力过载（RVPO）时右心室功能障碍是一种可逆的、负荷依赖的现象，而右心室固有的收缩功能不受影响。然而，我们已经证明：1)在RVPO 60 min后，尽管加载条件归一化，内征RV收缩函数仍然很低；2)这种功能障碍发生在没有右心室缺血的情况下；3)半胱氨酸蛋白酶钙蛋白酶的激活与右心室功能障碍同时发生；4)半胱氨酸蛋白酶抑制剂MDL-28170可减轻RVPO期间的RV功能障碍。我们的初步蛋白质组学分析表明，肌球蛋白重链在RVPO期间被降解。我们建议使用蛋白质组学方法来鉴定在右心室功能障碍发展过程中激活的特定蛋白酶；体内抑制剂实验将用于确定其机制的重要性。了解RVPO中RV功能障碍的机制是开发治疗这种具有挑战性的疾病的特异性疗法的关键。

DESCRIPTION (provided by applicant): Right heart failure due to acute pressure overload is a major cause of morbidity and mortality in conditions such as pulmonary embolism, hypoxic pulmonary vasoconstriction, and after cardiopulmonary bypass and heart transplantation. It was previously thought that right ventricular (RV) dysfunction during acute pressure overload (RVPO) was a reversible, load-dependent phenomenon, and that intrinsic RV contractile function was unaffected. However, we have shown that 1) intrinsic RV contractile function remains depressed despite normalization of loading conditions after 60 min RVPO; 2) this dysfunction occurs in the absence of RV ischemia; 3) activation of the cysteine protease calpain occurs coincident with the RV dysfunction; 4) the cysteine protease inhibitor MDL-28170 attenuates RV dysfunction during RVPO. Our preliminary proteomics analysis suggests that myosin heavy chain is degraded during RVPO. We propose using a proteomics approach to identify specific proteases activated during the development of RV dysfunction; in vivo inhibitor experiments will then be used to determine their mechanistic importance. Understanding the mechanism of RV dysfunction in RVPO is key to developing specific therapies for treatment of this challenging condition.