title: Mitochondrial reprogramming induced by CaMKIIδ mediates hypertrophy decompensation.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From 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.).
authors.forename: B Daan
authors.initials: BD
authors.lastname: Westenbrink
authors.affiliation: From 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.).
authors.forename: Haiyun
authors.initials: H
authors.lastname: Ling
authors.affiliation: From 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.).
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: From 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.).
authors.forename: Charles B B
authors.initials: CB
authors.lastname: Gray
authors.affiliation: From 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.).
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Zambon
authors.affiliation: From 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.).
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.affiliation: From 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.).
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: From 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.).
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: From 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.).
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.affiliation: From 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.).
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: From 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.).
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: From 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.).
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.affiliation: From 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.
authors.forename: Joan
authors.initials: J
authors.lastname: Heller Brown
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D018450:Disease Progression; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000209:etiology* / Q000503:physiopathology; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics; D017354:Point Mutation; D011312:Pressure; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species; D017423:Sequence Analysis, RNA; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D000071247:Uncoupling Protein 3; D000096926:Benzenesulfonamides
chemical_list: D000111:Acetylcysteine; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000071247:Uncoupling Protein 3; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: G-protein; Gq; calcium-calmodulin-dependent protein kinase type 2; heart failure; mitochondrial uncoupling protein 3; oxidative stress