Abstract 867: In vivo Inhibition of p38 MAPK Attenuates Angiotensin II-Induced Superoxide Anion Production and Target Organ Damage through Suppression of NAD(P)H Oxidase
Angiotensin II (Ang II) activates p38 mitogen-activated protein kinase (p38 MAPK) and increases reactive oxygen species (ROS). But how these processes are interrelated in vivo is not fully understood. In this study, we assess the hypothesis that in vivo inhibition of p38 MAPK with SB239063AN, a highly selective, orally active p38 MAPK inhibitor, attenuates Ang II-induced target organ damage by suppression of ROS production. Chronic Ang II-infusion into Sprague-Dawley rats (osmotic minipump) significantly increased aortic and cardiac phosphorylated p38 MAPK, aortic superoxide anion production (4-fold, n=9), and expression of NADPH oxidase subunits gp91phox/nox1-p65mox (~5-fold) compared with saline-infused rats. In addition, Ang II-infusion produced endothelial dysfunction, a progressive and sustained hypertension, and cardiac hypertrophy. Treatment with SB239063AN (800 ppm in the diet) significantly reduced the immunoreactivity of phosphorylated p38 MAPK in the aorta and in the heart. Interestingly, SB239063AN also reduced superoxide anion generation (by 57%, P<0.01, n=8) and markedly suppressed the up-regulation of NADPH oxidase subunits both gp91phox and Nox 1 (p65mox) mRNAs in the aorta (by 56% and 42%, respectively) and in the heart (51% and 57%, n=5– 6, respectively). Moreover, SB239063AN prevented endothelial dysfunction and blunted both the hypertension and cardiac hypertrophy induced by Ang II. In conclusion, in vivo inhibition of p38 MAPK with SB239063AN attenuates Ang II-induced cardiovascular target organ damage by down-regulation of NAD(P)H oxidase expression and suppression of ROS production.