| First Author | Westenbrink BD | Year | 2015 |
| Journal | Circ Res | Volume | 116 |
| Issue | 5 | Pages | e28-39 |
| PubMed ID | 25605649 | Mgi Jnum | J:251442 |
| Mgi Id | MGI:6101370 | Doi | 10.1161/CIRCRESAHA.116.304682 |
| Citation | Westenbrink BD, et al. (2015) Mitochondrial reprogramming induced by CaMKIIdelta mediates hypertrophy decompensation. Circ Res 116(5):e28-39 |
| abstractText | RATIONALE: Sustained activation of Galphaq 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. Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIdelta) is activated downstream of Gq, and overexpression of Gq and CaMKIIdelta recapitulates hypertrophy decompensation. OBJECTIVE: To determine whether CaMKIIdelta contributes to hypertrophy decompensation provoked by Gq. METHODS AND RESULTS: Compared with Gq mice, compound Gq/CaMKIIdelta 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 CaMKIIdelta 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 approximately 40% of these genes by CaMKIIdelta deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIdelta deletion or inhibition, as was peroxisome proliferator-activated receptor alpha. The protective effects of CaMKIIdelta 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 CaMKIIdelta. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor alpha and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIdelta deletion. CONCLUSIONS: Mitochondrial gene reprogramming induced by CaMKIIdelta emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy. |
