Rationale: Sustained activation of Gq transgenic (Gq) signaling during pressure overload causes cardiac hypertrophy that ultimately progresses to dilated cardiomyopathy. The molecular events that drive hypertrophy decompensation are incompletely understood. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated downstream of Gq, and overexpression of Gq and CaMKII recapitulates hypertrophy decompensation.
Objective: To determine whether CaMKII contributes to hypertrophy decompensation provoked by Gq.
Methods and Results: Compared with Gq mice, compound Gq/CaMKII knockout mice developed a similar degree of cardiac hypertrophy but exhibited significantly improved left ventricular function, less cardiac fibrosis and cardiomyocyte apoptosis, and fewer ventricular arrhythmias. Markers of oxidative stress were elevated in mitochondria from Gq versus wild-type mice and respiratory rates were lower; these changes in mitochondrial function were restored by CaMKII deletion. Gq-mediated increases in mitochondrial oxidative stress, compromised membrane potential, and cell death were recapitulated in neonatal rat ventricular myocytes infected with constitutively active Gq and attenuated by CaMKII inhibition. Deep RNA sequencing revealed altered expression of 41 mitochondrial genes in Gq hearts, with normalization of approximate to 40% of these genes by CaMKII deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKII deletion or inhibition, as was peroxisome proliferator-activated receptor . The protective effects of CaMKII inhibition on reactive oxygen species generation and cell death were abrogated by knock down of uncoupling protein 3. Conversely, restoration of uncoupling protein 3 expression attenuated reactive oxygen species generation and cell death induced by CaMKII. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKII deletion.
Conclusions: Mitochondrial gene reprogramming induced by CaMKII emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.