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Circ Res. 2015 Feb 27;116(5):e28-39. doi: 10.1161/CIRCRESAHA.116.304682. Epub 2015 Jan 20.

Mitochondrial reprogramming induced by CaMKIIδ mediates hypertrophy decompensation.

Author information

  • 1From the Department of Pharmacology (B.D.W., H.L., A.S.D., C.B.B.G., A.C.Z., A.N.M., J.H.B.), Department of Medicine (N.D.D., K.L.P., Y.G.), and Biomedical Sciences Graduate Program (C.B.B.G.), University of California San Diego; School of Internal Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO (S.J.M., G.W.D.); Department of Cardiology, University Medical Center Groningen, Unversity of Groningen, Groningen, The Netherlands (B.D.W.).
  • 2From the Department of Pharmacology (B.D.W., H.L., A.S.D., C.B.B.G., A.C.Z., A.N.M., J.H.B.), Department of Medicine (N.D.D., K.L.P., Y.G.), and Biomedical Sciences Graduate Program (C.B.B.G.), University of California San Diego; School of Internal Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO (S.J.M., G.W.D.); Department of Cardiology, University Medical Center Groningen, Unversity of Groningen, Groningen, The Netherlands (B.D.W.) jhbrown@ucsd.edu.

Abstract

RATIONALE:

Sustained activation of Gαq 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 δ (CaMKIIδ) is activated downstream of Gq, and overexpression of Gq and CaMKIIδ recapitulates hypertrophy decompensation.

OBJECTIVE:

To determine whether CaMKIIδ contributes to hypertrophy decompensation provoked by Gq.

METHODS AND RESULTS:

Compared with Gq mice, compound Gq/CaMKIIδ 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 CaMKIIδ 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 ≈40% of these genes by CaMKIIδ deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKIIδ deletion or inhibition, as was peroxisome proliferator-activated receptor α. The protective effects of CaMKIIδ 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 CaMKIIδ. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator-activated receptor α and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKIIδ deletion.

CONCLUSIONS:

Mitochondrial gene reprogramming induced by CaMKIIδ emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.

KEYWORDS:

G-protein; Gq; calcium-calmodulin-dependent protein kinase type 2; heart failure; mitochondrial uncoupling protein 3; oxidative stress

PMID:
25605649
PMCID:
PMC4344921
DOI:
10.1161/CIRCRESAHA.116.304682
[PubMed - indexed for MEDLINE]
Free PMC Article

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