Effects of p38 MAPK inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production
Effects of p38 MAPK inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production
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DOI：
10.1097/fjc.0b013e318046f34a
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发表时间：
2007-06-01
影响因子：
3
通讯作者：
Yue, Tian-Li
中科院分区：
文献类型：
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作者：
Bao, Weike;Behm, David J.;Yue, Tian-Li
血管紧张素II(Ang II)激活p38丝裂原活化蛋白激酶(P38 Mark)，增加活性氧(ROS)，但体内这种关系的本质还不完全清楚。我们评估了SB239063AN，一种高选择性、口服活性的p38 MAPK抑制剂，对Ang II依赖型高血压、靶器官损害和ROS产生的影响。给SD大鼠和MAPKAP-2基因敲除小鼠灌胃Ang II，Ang II能增加心脏和主动脉中p38MAPK的磷酸化水平。主动脉超氧阴离子生成量和NAD(P)H氧化酶亚单位gp91(Phox)表达分别增加4倍和5倍。此外，血管紧张素转换酶II输注导致内皮功能障碍、进行性和持续性高血压以及心肌肥厚。SB239063AN(800ppm饲料中)可显著降低心脏和主动脉中p38MAPK的磷酸化水平，使超氧阴离子生成减少57%(P<；0.01)，显著抑制gp91(Phox)mRNA的表达，防止内皮功能障碍，钝化高血压和心肌肥厚。MAPKAP激酶-2基因敲除小鼠的血管紧张素Ⅱ依赖性高血压也显著减轻。结果提示，血管紧张素Ⅱ诱导的高血压、器官损伤和ROS的产生可能是由p38MAPK介导的，抑制p38MAPK可能为心血管疾病的治疗提供了新的途径。
Angiotensin II (Ang II) activates p38 mitogen-activated protein kinase (p38 MARK) and increases reactive oxygen species (ROS), but the nature of the relationship in vivo is not fully understood. We assess the effect of SB239063AN, a highly selective, orally active, p38 MAPK inhibitor, on Ang II-dependent hypertension, target-organ damage and ROS production. Sprague-Dawley rats and MAPKAP kinase-2 knockout mice were infused with Ang II. Ang II infusion increased the levels of phosphorylated p38 MAPK in the heart and aorta. Production of superoxide anion and expression of NAD(P)H oxidase subunit gp91(phox) in the aorta were increased 4- and 5-fold, respectively. In addition, Ang II infusion led to endothelial dysfunction, progressive and sustained hypertension, and cardiac hypertrophy. Treatment with SB239063AN (800 ppm in the diet) significantly attenuated the levels of phosphorylated p38 MAPK in the heart and aorta, reduced superoxide anion generation by 57% (P < 0.01), markedly suppressed gp91(phox) mRNA expression, prevented endothelial dysfunction, and blunted both the hypertension and cardiac hypertrophy. Ang II-dependent hypertension was also significantly allenuated in MAPKAP kinase-2 knockout mice. The results suggest that Ang II induced hypertension, organ damage, and ROS production are possibly mediated by p38 MAPK and inhibition of p38 MAPK may offer a therapeutic approach for cardiovascular disease.