Effects of p38 MAPK Inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production.
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.
Bao
Weike
W
Department of Investigative and Cardiac Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Weike_2_Bao@gsk.com
Behm
David J
DJ
Nerurkar
Sandhya S
SS
Ao
Zhaohui
Z
Bentley
Ross
R
Mirabile
Rosanna C
RC
Johns
Douglas G
DG
Woods
Tina N
TN
Doe
Christopher P A
CP
Coatney
Robert W
RW
Ohlstein
Jason F
JF
Douglas
Stephen A
SA
Willette
Robert N
RN
Yue
Tian-Li
TL
D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000099190:MAP-Kinase-Activated Kinase 2
D000804:Angiotensin II; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D013481:Superoxides; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C502576:SB-239063AN; C500593:Cybb protein, rat