Calpain Activation and Inhibition in Right Heart Failure

描述（由申请方提供）：急性压力超负荷引起的右心衰竭是肺栓塞、缺氧性肺血管收缩、心肺转流术和心脏移植后发病和死亡的主要原因。以前认为，在急性压力超负荷（RVPO）过程中，右心室（RV）功能障碍是一种可逆的、负荷依赖性的现象，而固有的RV收缩功能不受影响。然而，我们已经表明：1）尽管60分钟RVPO后负荷条件正常化，但固有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）半胱氨酸蛋白酶钙蛋白酶的激活与RV功能障碍同时发生; 4）半胱氨酸蛋白酶抑制剂MDL-28170在RVPO期间减弱RV功能障碍。我们初步的蛋白质组学分析表明，肌球蛋白重链降解RVPO。我们建议使用蛋白质组学的方法来确定特定的蛋白酶在RV功能障碍的发展过程中激活，体内抑制剂实验将被用来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.