Calreticulin Induces Dilated Cardiomyopathy

Background: Calreticulin, a Ca2+-buffering chaperone of the endoplasmic reticulum, is highly expressed in the heart and is essential for cardiac development. After birth, the calreticulin gene is sharply down regulated in the heart, thus, adult hearts have negligible levels of calreticulin. In this study we tested the role of calreticulin in the adult heart. Methodology/PrincipalFindings: We generated an inducible transgenic mouse in which calreticulin is targeted to cardiac tissue using a Cre/loxP system and can be up-regulated in adult hearts. Echocardiography analysis of hearts transgenic mice expressing calreticulin revealed impaired left ventricular systolic and diastolic function and impaired valve function. There was altered expression of Ca2+ signaling molecules and the gap junction proteins, Connexin 43 and Sarcoplasmic reticulum associated Ca2+-handling proteins (including the cardiac ryanodine receptor, sarco/reticulum Ca2+-ATPase, and cardiac calsequestrin) were down-regulated in the transgenic hearts with increased of calreticulin.Conclusions/Significance: We show that in adult heart, up-regulated expression of calreticulin induces cardiomyopathy vivo leading to heart failure. This is due to an alternation in changes in a subset of Ca2+ handling genes, gap components and left ventricle remodeling.