期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 49, 期 1, 页码 25-32出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2010.03.013
关键词
Arrhythmia; CaMKII; SR Ca leak; heart failure; ryanodine receptor
资金
- NHLBI NIH HHS [R01 HL071893-07, R01 HL071893, R01 HL064724, R37 HL030077] Funding Source: Medline
Increased cardiac ryanodine receptor (RyR)-dependent diastolic SR Ca leak is present in heart failure and in conditions when adrenergic tone is high Increasing Ca leak from the SR could result in spontaneous Ca wave (SCaW) formation SCaWs activate the inward Na/Ca exchanger (NCX) current causing a delayed afterdepolarization (DAD), potentially leading to arrhythmia. Here we examine SCaWs in ventricular myocytes isolated from failing and healthy rabbit hearts Myocytes from healthy hearts did not exhibit SCaWs under baseline conditions versus 43% of those exposed to isoproterenol (ISO) This ISO-induced increase in activity was reversed by inhibition of Ca-calmodulin-dependent protein kinase II (CaMKII) by KN93. Inhibition of cAMP-dependent protein kinase (PKA) by H89 had no observed effect Of myocytes treated with forskolin 50% showed SCaW activity, attributable to a large Increase in SR Ca load ([Ca](SRT)) versus control. At similar [Ca](SRT) (121 mu M) myocytes treated with ISO plus KN93 had significantly fewer SCaWs versus those treated with ISO or ISO plus H89 (0.2 +/- 0.28 vs. 1.29 +/- 0.28 and 1.29 +/- 0.39 SCaWs cell(-1), respectively). In myocytes isolated from failing hearts ISO induced an increase in the percentage of cells generating SCaWs vs baseline (74% vs 11%) with no increase in [Ca](SRT) Inhibiting CaMKII reversed this effect (14%). At similar [Ca](SRT) (71 mu M) myocytes treated with ISO or ISO plus H89 had significantly more SCaWs per cell vs untreated (2.5 +/- 0.5, 1.6 +/- 0.7 vs 0.36 +/- 0.3, respectively) Treatment with ISO plus KN93 completely abolished this effect The evidence suggests the ISO-dependent increase in SCaW activity in both healthy and failing myocytes is CaMKII-dependent, implicating CaMKII in arrhythmogenesis (C) 2010 Elsevier Ltd All rights reserved.
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