{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T14:18:30Z","timestamp":1793024310078,"version":"4.5.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,2,27]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Sustained activation of G\u03b1q 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\n                      <jats:sup>2+<\/jats:sup>\n                      \/calmodulin-dependent protein kinase II \u03b4 (CaMKII\u03b4) is activated downstream of Gq, and overexpression of Gq and CaMKII\u03b4 recapitulates hypertrophy decompensation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>To determine whether CaMKII\u03b4 contributes to hypertrophy decompensation provoked by Gq.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Compared with Gq mice, compound Gq\/CaMKII\u03b4 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\u03b4 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 \u224840% of these genes by CaMKII\u03b4 deletion. Uncoupling protein 3 was markedly downregulated in Gq or by Gq expression in neonatal rat ventricular myocytes and reversed by CaMKII\u03b4 deletion or inhibition, as was peroxisome proliferator\u2013activated receptor \u03b1. The protective effects of CaMKII\u03b4 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\u03b4. Our in vivo studies further demonstrated that pressure overload induced decreases in peroxisome proliferator\u2013activated receptor \u03b1 and uncoupling protein 3, increases in mitochondrial protein oxidation, and hypertrophy decompensation, which were attenuated by CaMKII\u03b4 deletion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Mitochondrial gene reprogramming induced by CaMKII\u03b4 emerges as an important mechanism contributing to mitotoxicity in decompensating hypertrophy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.116.304682","type":"journal-article","created":{"date-parts":[[2015,1,21]],"date-time":"2015-01-21T01:53:36Z","timestamp":1421805216000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":64,"title":["Mitochondrial Reprogramming Induced by CaMKII\u03b4 Mediates Hypertrophy Decompensation"],"prefix":"10.1161","volume":"116","author":[{"given":"B. Daan","family":"Westenbrink","sequence":"first","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyun","family":"Ling","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajit S.","family":"Divakaruni","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles B.B.","family":"Gray","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander C.","family":"Zambon","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy D.","family":"Dalton","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk L.","family":"Peterson","sequence":"additional","affiliation":[{"name":"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.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusu","family":"Gu","sequence":"additional","affiliation":[{"name":"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 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