Abstract 922: Cardiac-specific Deletion of Orai3 Channel Causes Dilated Cardiomyopathy

Abstract

Background: Calcium (Ca2+) signalling is a vital regulator of cardiac myocyte function. Defective cellular calcium handling is widely recognized as a significant patho-physiological event in the contractile dysfunction of the failing heart. Orai3 is a newly discovered calcium channels that participate in the voltage-independent calcium currents in the mycardium. However, its role in the heart remain uncharacterized. Methods and Results: Here, we show that disruption of Orai3 function in murine cardiomyocytes leads to decompensated dilated cardiomyopathy. Echocardiographic analysis supported by histological examinations revealed that 4-month-old Orai3 knockout (KO) mice have signs of dilated cardiomyopathy denoted by a loss of EF and a thinner left ventricular posterior wall and septum, with significant fibrosis, whereas in the younger animals only a thinner septum could be observed. In both genders, most mice died within six months after birth. Myocardial samples that underwent electron microscopy and immunohistochemical analysis showed myofilament changes in Orai3 KO mice with misexpression of cardiac contractile proteins and profound sarcomere disarray. Transverse aortic constriction (TAC) was used as a chronic stressor on the younger mice to determine whether the ability to compensate against a pathologic insult is compromised in the Orai3 KO heart. Orai3 KO mice presented with significantly reduced systolic function and ventricular dilation that deteriorated into congestive HF within 4 weeks post-surgery, while constricted WT hearts remained well-adapted throughout. Conclusions: Thus, our results identify Orai3 critical role in adult cardiac function and demonstrate a novel cardioprotective role of Orai3 against cardiac pressure overload-induced heart failure.