p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat
p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat
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DOI：
10.1016/j.jacc.2004.07.038
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发表时间：
2004-10-19
影响因子：
24
通讯作者：
Krum, H
中科院分区：
文献类型：
--
作者：
See, F;Thomas, W;Krum, H
本研究的目的是检测p38丝裂原活化蛋白激酶（MAPK）抑制剂RWJ-67657（RWJ）对大鼠心肌梗死（MI）后左心室（LV）功能障碍和重构的影响。（冠状动脉结扎），大鼠接受RWJ（50 mg/天，通过管饲，n = 8，MI + RWJ）或媒介物（通过管饲，n = 8，MI + V）21天。在第6天、给药开始前和第27天进行超声心动图检查。在第28天进行体内血液动力学测量。假手术大鼠作为controls. Results左室舒张末期压和肺/体重比降低，而左室压力上升的最大速率增加对假手术的MI+RWJ与MI+ V相比，基线超声心动图研究表明，MI大鼠均匀的左室重构和功能障碍。短轴缩短率（FS）在MI+V中进一步恶化，而在MI+RWJ中保留FS。在MI+RWJ中抑制了MI+V中观察到的进行性LV扩张和梗死扩展。与MI+ V相比，MI+RWJ还显示梗死周围和非梗死区的心肌细胞肥大增加，心肌胶原和α-平滑肌肌动蛋白（SMA）免疫反应性降低。RWJ在体内的抗纤维化作用可能反映了对心脏成纤维细胞的直接作用，因为RWJ减弱了转化生长因子β-1刺激的胶原合成和分离的心脏成纤维细胞中的α-SMA表达。RWJ还保护培养的心肌细胞过氧化氢诱导apoptosis.CONCLUSIONS RWJ-67657治疗后MI对LV重塑和功能障碍有有益的影响，支持p38 MAPK在这些过程中的病理细胞信号传导及其抑制作为一种新的治疗方法的关键作用。(C)2004年，美国心脏病学会基金会。
OBJECTIVES The aim of this study was to examine the effect of the p38 mitogen-activated protein kinase (MAPK) inhibitor, RWJ-67657 (RWJ), on left ventricular (LV) dysfunction and remodeling post-myocardial infarction (MI) in rats.BACKGROUND p38 MAPK signaling has been implicated in the progression of chronic heart failure.METHODS From day 7 post-MI (coronary artery ligation), rats received either RWJ (50 mg/day, by gavage, n = 8, MI + RWJ) or vehicle (by gavage, n = 8, MI + V) for 21 days. Echocardiography was performed on day 6, before the commencement of treatment, and on day 27. In vivo hemodynamic measurements were made on day 28. Sham-operated rats served as controls.RESULTS The LV end-diastolic pressure and lung/body weight ratio were reduced, whereas the maximum rate of rise of LV pressure was increased towards sham levels in MI+RWJ compared with MI+V. Baseline echocardiographic studies demonstrated uniform LV remodeling and dysfunction in MI rats. Fractional shortening (FS) further deteriorated in MI+V, whereas FS was preserved in MI+RWJ. Progressive LV dilation and infarct expansion observed in MI+V were inhibited in MI+RWJ. MI+RWJ also demonstrated increased myocyte hypertrophy in the peri-infarct and non-infarct zones, and reduced myocardial collagen and a-smooth muscle actin (SMA) immunoreactivity compared with MI+V. The antifibrotic effects of RWJ in vivo may reflect direct effects on cardiac fibroblasts, because RWJ attenuated transforming growth factor beta-1-stimulated collagen synthesis and alpha-SMA expression in isolated cardiac fibroblasts. RWJ also protected cultured myocytes from hydrogen peroxide-induced apoptosis.CONCLUSIONS RWJ-67657 treatment post-MI had beneficial effects on LV remodeling and dysfunction, supporting a key role for p38 MAPK in pathologic cell signaling in these processes and its inhibition as a novel therapy. (C) 2004 by the American College of Cardiology Foundation.