PMID- 26080362 OWN - NLM STAT- MEDLINE DCOM- 20160517 LR - 20230713 IS - 1095-8584 (Electronic) IS - 0022-2828 (Print) IS - 0022-2828 (Linking) VI - 85 DP - 2015 Aug TI - CaMKIIdelta mediates beta-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic beta-adrenergic stimulation. PG - 282-91 LID - S0022-2828(15)00193-5 [pii] LID - 10.1016/j.yjmcc.2015.06.007 [doi] AB - Chronic activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the deleterious effects of beta-adrenergic receptor (beta-AR) signaling on the heart, in part, by enhancing RyR2-mediated sarcoplasmic reticulum (SR) Ca(2+) leak. We used CaMKIIdelta knockout (CaMKIIdelta-KO) mice and knock-in mice with an inactivated CaMKII site S2814 on the ryanodine receptor type 2 (S2814A) to investigate the involvement of these processes in beta-AR signaling and cardiac remodeling. Langendorff-perfused hearts from CaMKIIdelta-KO mice showed inotropic and chronotropic responses to isoproterenol (ISO) that were similar to those of wild type (WT) mice; however, in CaMKIIdelta-KO mice, CaMKII phosphorylation of phospholamban and RyR2 was decreased and isolated myocytes from CaMKIIdelta-KO mice had reduced SR Ca(2+) leak in response to isoproterenol (ISO). Chronic catecholamine stress with ISO induced comparable increases in relative heart weight and other measures of hypertrophy from day 9 through week 4 in WT and CaMKIIdelta-KO mice, but the development of cardiac fibrosis was prevented in CaMKIIdelta-KO animals. A 4-week challenge with ISO resulted in reduced cardiac function and pulmonary congestion in WT, but not in CaMKIIdelta-KO or S2814A mice, implicating CaMKIIdelta-dependent phosphorylation of RyR2-S2814 in the cardiomyopathy, independent of hypertrophy, induced by prolonged beta-AR stimulation. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Grimm, Michael AU - Grimm M AD - Department of Pharmacology, University of California, San Diego, CA, USA. FAU - Ling, Haiyun AU - Ling H AD - Department of Pharmacology, University of California, San Diego, CA, USA. FAU - Willeford, Andrew AU - Willeford A AD - Department of Pharmacology, University of California, San Diego, CA, USA. FAU - Pereira, Laetitia AU - Pereira L AD - Department of Pharmacology, University of California, Davis, CA, USA. FAU - Gray, Charles B B AU - Gray CB AD - Department of Pharmacology, University of California, San Diego, CA, USA. FAU - Erickson, Jeffrey R AU - Erickson JR AD - Department of Pharmacology, University of California, Davis, CA, USA. FAU - Sarma, Satyam AU - Sarma S AD - Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA. FAU - Respress, Jonathan L AU - Respress JL AD - Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA. FAU - Wehrens, Xander H T AU - Wehrens XH AD - Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA. FAU - Bers, Donald M AU - Bers DM AD - Department of Pharmacology, University of California, Davis, CA, USA. FAU - Brown, Joan Heller AU - Brown JH AD - Department of Pharmacology, University of California, San Diego, CA, USA. Electronic address: jhbrown@ucsd.edu. LA - eng GR - HL091947/HL/NHLBI NIH HHS/United States GR - P01 HL080101/HL/NHLBI NIH HHS/United States GR - R01 HL092097/HL/NHLBI NIH HHS/United States GR - HL089598/HL/NHLBI NIH HHS/United States GR - T32 HL007676/HL/NHLBI NIH HHS/United States GR - R01 HL091947/HL/NHLBI NIH HHS/United States GR - R25 GM056929/GM/NIGMS NIH HHS/United States GR - 2 T32-GM007752/GM/NIGMS NIH HHS/United States GR - T32 GM007752/GM/NIGMS NIH HHS/United States GR - HL28143/HL/NHLBI NIH HHS/United States GR - HL117641/HL/NHLBI NIH HHS/United States GR - R01 HL105242/HL/NHLBI NIH HHS/United States GR - R01 HL117641/HL/NHLBI NIH HHS/United States GR - T32-HL07676/HL/NHLBI NIH HHS/United States GR - R01 HL089598/HL/NHLBI NIH HHS/United States GR - R37 HL028143/HL/NHLBI NIH HHS/United States GR - P01 HL080101-05/HL/NHLBI NIH HHS/United States GR - R01 HL028143/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150614 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (Adrenergic beta-Agonists) RN - 0 (Calcium-Binding Proteins) RN - 0 (Ryanodine Receptor Calcium Release Channel) RN - 0 (phospholamban) RN - 0 (ryanodine receptor 2. mouse) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - L628TT009W (Isoproterenol) RN - SY7Q814VUP (Calcium) SB - IM MH - Adrenergic beta-Agonists/*pharmacology MH - Animals MH - Calcium/metabolism MH - Calcium Signaling MH - Calcium-Binding Proteins MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*physiology MH - Cardiomegaly/enzymology MH - Cardiomyopathies/enzymology MH - Cells, Cultured MH - Fibrosis MH - Isoproterenol/pharmacology MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Myocytes, Cardiac/drug effects/enzymology MH - Phosphorylation MH - *Protein Processing, Post-Translational MH - Ryanodine Receptor Calcium Release Channel/*metabolism MH - Sarcoplasmic Reticulum/metabolism MH - Ventricular Remodeling PMC - PMC4530053 MID - NIHMS708923 OTO - NOTNLM OT - Beta-adrenergic OT - CaMKII OT - Fibrosis OT - Hypertrophy OT - Phosphorylation EDAT- 2015/06/17 06:00 MHDA- 2016/05/18 06:00 PMCR- 2016/08/01 CRDT- 2015/06/17 06:00 PHST- 2014/12/24 00:00 [received] PHST- 2015/06/06 00:00 [revised] PHST- 2015/06/09 00:00 [accepted] PHST- 2015/06/17 06:00 [entrez] PHST- 2015/06/17 06:00 [pubmed] PHST- 2016/05/18 06:00 [medline] PHST- 2016/08/01 00:00 [pmc-release] AID - S0022-2828(15)00193-5 [pii] AID - 10.1016/j.yjmcc.2015.06.007 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2015 Aug;85:282-91. doi: 10.1016/j.yjmcc.2015.06.007. Epub 2015 Jun 14.