期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 85, 期 -, 页码 282-291出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.06.007
关键词
Beta-adrenergic; CaMKII; Fibrosis; Hypertrophy; Phosphorylation
资金
- NIH [P01 HL080101-05, HL28143, HL089598, HL091947, HL117641]
- American Heart Association Post-Doctoral Fellowship [0825268F]
- AHA postdoctoral fellowship
- Fondation Leducq (Alliance for CaMKII Signaling in Heart)
- [2 T32-GM007752]
- [T32-HL07676]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL028143, R01HL117641, R37HL028143, R01HL091947, T32HL007676, R01HL092097, R01HL089598, R01HL105242, P01HL080101] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007752, R25GM056929] Funding Source: NIH RePORTER
Chronic activation of Ca2+/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) Ca2+ leak. We used CaMKII delta knockout (CaMKII delta-KO) mice and knockin 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 CaMKII delta-KO mice showed inotropic and chronotropic responses to isoproterenol (ISO) that were similar to those of wild type (WT) mice; however, in CaMKII delta-KO mice, CaMKII phosphorylation of phospholamban and RyR2 was decreased and isolated myocytes from CaMKII delta-KO mice had reduced SR Ca2+ 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 CaMKII delta-KO mice, but the development of cardiac fibrosis was prevented in CaMKII delta-KO animals. A 4-week challenge with ISO resulted in reduced cardiac function and pulmonary congestion in WT, but not in CaMKII delta-KO or S2814A mice, implicating CaMKII delta-dependent phosphorylation of RyR2-S2814 in the cardiomyopathy, independent of hypertrophy, induced by prolonged beta-AR stimulation. (C) 2015 Elsevier Ltd. All rights reserved.
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