Calpain Activation and Inhibition in Right Heart Failure

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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.