期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 300, 期 5, 页码 H1669-H1677出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00272.2010
关键词
ischemia; small heat shock protein; heat shock protein 27; p38 mitogen-activated protein kinase
资金
- National Heart, Lung, and Blood Institute [5K99 HL093352-02, 5R01 HL046716-17]
Clements RT, Feng J, Cordeiro B, Bianchi C, Sellke FW. p38 MAPK-dependent small HSP27 and (B-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest. Am J Physiol Heart Circ Physiol 300: H1669-H1677, 2011. First published February 25, 2011; doi:10.1152/ajpheart.00272.20.10. We previously demonstrated that myocardial p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27) are phosphorylated following cardioplegic arrest in patients undergoing cardiac surgery and con-elate with reduced cardiac function. The following studies were performed to determine whether inhibition of p38 MAPK and/or overexpression of nonphosphorylatable HSP27 improves cardiac function following cardioplegic arrest. Langendorff-perfused isolated rat hearts were subjected to 2 h of intermittent cold cardioplegia followed by 30 mitt of reperfusion. Hearts were treated with (CP+SB) or without (CP) the p38 MAPK inhibitor SB-203580 (5 mu M) supplied in the cardioplegia. Sham-treated hearts served as controls. In separate experiments, isolated rat ventricular myocytes infected with either green :fluorescent protein (GFP) or a nonphosphorylatable HSP27 mutant (3A-HSP27) were subjected to 3 h of cold hypoxic cardioplegia and simulated reperfusion (CP) followed by video microscopy and length change measurements. Baseline parameters of cardiac function were similar between groups [left ventricular developed pressure (LVDP), 119 +/- 4.9 mmHg; positive and negative first derivatives of LV pressure (+/- dP/dt), 3,139 +/- 245 and 2, 314 +/- 110 mmHg/s] CP resulted in reduced cardiac function (LVDP, 72.2 +/- 5.8 mmHg; +/- dP/dt, 2,076 +/- 231 and -1,317 +/- 156 mmHg/s) compared with baseline. Treatment with 5 mu M SB-203580 significantly improved CP-induced cardiac function (LVDP, 101.9 +/- 0 mmHg: +/-dP/dt, 2,836 +/- 163 and -2,108 +/- 120 mmHg/s; P = 0.03, 0.01, and 0.04, CP+SB vs. CP). Inhibition of p38 MAPK significantly lowered CP-induced p38 MAPK, HSP27, and alpha B-crystallin (cryAB) phosphorylation. In vitro CP decreased myocyte length changes from 10.3 +/- 1.5% (GFP) to 5.7 +/- 0.8% (GFP+CP). Infection with 3A-HSP27 completely rescued CP-induced decreased myocyte contraction (11.1 +/- 1.0%). However, infection with 3A-HSP27 did not block the endogenous HSP27 response. We conclude that inhibition of p38 MAPK and subsequent HSP27 and cryAB phosphorylation and/or overexpression of nonphosphorylatable HSP27 significantly improves cardiac performance following cardioplegic arrest. Modulation of HSP27 phosphorylation may improve myocardial stunning following cardiac surgery.
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