Selective inhibition of p38α MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury
Selective inhibition of p38α MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury
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DOI：
10.1152/ajpheart.00043.2006
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发表时间：
2006-10-01
影响因子：
4.8
通讯作者：
Protter, Andrew A.
中科院分区：
文献类型：
--
作者：
Li, Zhihe;Ma, Jing Ying;Protter, Andrew A.
选择性抑制p38 α MAPK改善大鼠心肌损伤模型的心功能并减少心肌细胞凋亡美国生理学杂志心脏循环生理学291：H1972-H1977，2006年。首次发表于2006年6月2日; doi：10.1152/ajpheart. 00043.2006.- p38 MAPK在心脏疾病中被激活，可能与心肌损伤和心功能恶化有关。在大鼠心肌损伤模型中，我们研究了使用新型口服p38 α MAPK抑制剂抑制p38 MAPK的心脏保护作用。大鼠用N-ω-硝基-L-精氨酸甲酯（（L-）NAME，40 mg . kg（-1）。第（-1）天）加1%盐的饮用水中14天，ANG II（0.5 mg.kg（-1）.第（-1）天）中3天。选择性p38 α MAPK抑制剂SD-282（60 mg/kg）口服给药，每天两次，持续4天，在ANG II给药前1天开始。通过改善心功能、减少炎性细胞浸润和心肌细胞凋亡来评价p38 α MAPK抑制的心脏保护作用。SD-282显著改善心功能，表现为每搏输出量、心输出量、射血分数和每搏功增加以及动脉弹性显著降低。SD-282还显著减少巨噬细胞浸润，这通过心肌中特异性标记物艾德-1阳性染色细胞的减少来判断（P < 0.05）。此外，SD-282可抑制caspase-3免疫组化染色显示的心肌细胞凋亡，这一作用可能有助于减轻成像分析评估的心肌损伤（两种情况下均P < 0.05）。数据表明，p38 α MAPK可能在心功能不全的发病机制中起关键作用。抑制p38 α MAPK可作为一种新的心脏保护策略，用于减轻急性心血管疾病（如心肌梗死）中发生的炎症反应和心脏功能恶化。
Selective inhibition of p38 alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. Am J Physiol Heart Circ Physiol 291: H1972-H1977, 2006. First published June 2, 2006; doi: 10.1152/ajpheart. 00043.2006.-p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38 alpha MAPK inhibitor. Rats were treated with N-omega-nitro-L-arginine methyl ester ((L-)NAME, 40 mg . kg(-1) . day(-1)) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg.kg(-1) .day(-1)) for 3 days. A selective p38 alpha MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38 alpha MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantly reduced macrophage infiltration as judged by reduction of a specific marker, ED-1-positive staining cells (P < 0.05) in the myocardium. Furthermore, cardiomyocyte apoptosis as indicated by caspase-3 immunohistochemical staining was abolished by SD-282, and this effect may contribute to the reduction of myocardial damage evaluated by imaging analysis (P < 0.05 in both cases). Data suggest that p38 alpha MAPK may play a critical role in the pathogenesis of cardiac dysfunction. Inhibition of p38 alpha MAPK may be used as a novel cardioprotective strategy in attenuation of inflammatory response and deterioration of cardiac function that occurs in acute cardiovascular disease such as myocardial infarction.