Cardiac‐Specific Deletion of Orai3 Leads to Severe Dilated Cardiomyopathy and Heart Failure in Mice

Abstract

Background Orai3 is a mammalian‐specific member of the Orai family (Orai1‒3) and a component of the store‐operated Ca2+ entry channels. There is little understanding of the role of Orai channels in cardiomyocytes, and its role in cardiac function remains unexplored. Thus, we developed mice lacking Orai1 and Orai3 to address their role in cardiac homeostasis. Methods and Results We generated constitutive and inducible cardiomyocyte‐specific Orai3 knockout (Orai3cKO) mice. Constitutive Orai3‐loss led to ventricular dysfunction progressing to dilated cardiomyopathy and heart failure. Orai3cKO mice subjected to pressure overload developed a fulminant dilated cardiomyopathy with rapid heart failure onset, characterized by interstitial fibrosis and apoptosis. Ultrastructural analysis of Orai3‐deficient cardiomyocytes showed abnormal M‐ and Z‐line morphology. The greater density of condensed mitochondria in Orai3‐deficient cardiomyocytes was associated with the upregulation of DRP1 (dynamin‐related protein 1). Cardiomyocytes isolated from Orai3cKO mice exhibited profoundly altered myocardial Ca2+ cycling and changes in the expression of critical proteins involved in the Ca2+ clearance mechanisms. Upregulation of TRPC6 (transient receptor potential canonical type 6) channels was associated with upregulation of the RCAN1 (regulator of calcineurin 1), indicating the activation of the calcineurin signaling pathway in Orai3cKO mice. A more dramatic cardiac phenotype emerged when Orai3 was removed in adult mice using a tamoxifen‐inducible Orai3cKO mouse. The removal of Orai1 from adult cardiomyocytes did not change the phenotype of tamoxifen‐inducible Orai3cKO mice. Conclusions Our results identify a critical role for Orai3 in the heart. We provide evidence that Orai3‐mediated Ca2+ signaling is required for maintaining sarcomere integrity and proper mitochondrial function in adult mammalian cardiomyocytes.

Keywords

• calcium signaling
• dilated cardiomyopathy
• ion channels
• Orai3