Abstract 18574: Mitochondrial Reprogramming By Camkiiδ Underlies Gq-induced Cardiomyopathy

Abstract

Background: Sustained activation of Gq signaling causes pressure overload hypertrophy, that inevitably decompensates as dilated cardiomyopathy. These molecular processes are recapitulated by cardiac overexpression of Gq (Gq-TG). Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIδ) may be a crucial regulator of this maladaptive response and we thus sought to determine if CaMKIIδ is required for the pathologic transformation of cardiac hypertrophy. Methods: Gq-TG mice were crossbred with CaMKIIδ knockout (CaMKIIδ-KO) mice to generate KO/TG mice. In addition, we studied the role of CaMKIIδ in the response of neonatal rat ventricular myocytes (NRVM) to constitutively activated Gαq (Ad-Q209L). Results: CaMKII activity was increased in hearts from Gαq transgenic mice and in NRVM infected with Ad-Q209L. CaMKIIδ deletion did not affect Gαq-induced hypertrophy in vitro and in vivo, but did result in a significant improvement of left ventricular function and reduced cardiac fibrosis. Deep RNA sequencing revealed marked reprogramming of mitochondrial genes in Gq-TG mice. Intriguingly, 41% of these mitochondrial mRNAs were normalized by CaMKIIδ deletion, including the ROS modulator uncoupling protein 3 (UCP3). Hearts of Gq transgenics showed increased oxidative stress, mitochondrial protein oxidation and a reduced mitochondrial respiration, all of which were normalized in KO/TG mice. The ability of Q209L to induce mitochondrial oxidative stress, mitochondrial membrane depolarization and cell death in NRVMs was also attenuated by CaMKII inhibition. UCP3 protein levels were reduced by Q209L and normalized with CaMKII inhibition. The protective effects of CaMKIIδ-inhibition on mitochondrial ROS production and cell death were abrogated by knock down of UCP3, consistent with a link between CaMKIIδ-induced repression of UCP3 and Gαq-induced ROS production. Conclusion: Mitochondrial reprogramming by CaMKIIδ is critically involved in the development of Gq-dependent cardiomyopathy, mediated in part by increased mitochondrial oxidative stress linked to transcriptional repression of UCP3.