Bao Weike, Behm David J, Nerurkar Sandhya S, Ao Zhaohui, Bentley Ross, Mirabile Rosanna C, Johns Douglas G, Woods Tina N, Doe Christopher P A, Coatney Robert W, Ohlstein Jason F, Douglas Stephen A, Willette Robert N, Yue Tian-Li
Department of Investigative and Cardiac Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
J Cardiovasc Pharmacol. 2007 Jun;49(6):362-8. doi: 10.1097/FJC.0b013e318046f34a.
Angiotensin II (Ang II) activates p38 mitogen-activated protein kinase (p38 MAPK) 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 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 mRNA expression, prevented endothelial dysfunction, and blunted both the hypertension and cardiac hypertrophy. Ang II-dependent hypertension was also significantly attenuated 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.
血管紧张素II（Ang II）激活p38丝裂原活化蛋白激酶（p38 MAPK）并增加活性氧（ROS），但体内这种关系的本质尚未完全明确。我们评估了一种高度选择性、口服活性的p38 MAPK抑制剂SB239063AN对Ang II依赖性高血压、靶器官损伤和ROS产生的影响。给Sprague-Dawley大鼠和MAPKAP激酶-2基因敲除小鼠输注Ang II。输注Ang II可增加心脏和主动脉中磷酸化p38 MAPK的水平。主动脉中超氧阴离子的产生和NAD(P)H氧化酶亚基gp91的表达分别增加了4倍和5倍。此外，输注Ang II导致内皮功能障碍、进行性和持续性高血压以及心脏肥大。用SB239063AN（饮食中800 ppm）治疗可显著降低心脏和主动脉中磷酸化p38 MAPK的水平，使超氧阴离子生成减少57%（P < 0.01），明显抑制gp91 mRNA表达，预防内皮功能障碍，并减轻高血压和心脏肥大。在MAPKAP激酶-2基因敲除小鼠中，Ang II依赖性高血压也显著减轻。结果表明，Ang II诱导的高血压、器官损伤和ROS产生可能由p38 MAPK介导，抑制p38 MAPK可能为心血管疾病提供一种治疗方法。
