Calpain Activation and Inhibition in Right Heart Failure

描述(由申请人提供)：急性压力超负荷导致的右心衰竭是肺栓塞、缺氧性肺血管收缩以及体外循环和心脏移植后发病率和死亡率的主要原因。以往的研究认为，急性压力超负荷(RVPO)时的右室功能障碍是一种可逆的负荷依赖性现象，其固有的右室收缩功能不受影响。然而，我们已经证明：1)尽管60min的RVPO负荷条件恢复正常，固有的RV收缩功能仍然受到抑制；2)这种功能障碍在没有RV缺血的情况下发生；3)半胱氨酸蛋白酶的激活与RV功能障碍的发生是一致的；4)半胱氨酸蛋白酶抑制剂MDL-28170可以减轻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过程中被降解。我们建议使用蛋白质组学的方法来确定在RV功能障碍发展过程中激活的特定蛋白水解酶；然后将使用体内抑制剂实验来确定它们的机制重要性。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定疗法的关键。

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.