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p38 MAPK inhibition prevents angiotensin II‐induced elevation of arginase (ARG) activity and impaired vasorelaxation
Author(s) -
Shatanawi Alia,
Romero M J,
Chandra S,
Yao L,
Toque H Flores,
Iddings J A,
Caldwell R B,
Caldwell R W
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.959.2
Subject(s) - angiotensin ii , arginase , p38 mitogen activated protein kinases , mapk/erk pathway , chemistry , endocrinology , medicine , renin–angiotensin system , phosphorylation , nitric oxide , in vivo , protein kinase a , kinase , nitric oxide synthase , pharmacology , arginine , biology , biochemistry , receptor , blood pressure , amino acid , microbiology and biotechnology
Elevated angiotensin II (Ang II) levels contribute to vascular endothelial dysfunction (ED) in a variety of diseases. Enhanced ARG activity contributes to ED by decreasing L‐arginine availability to NO synthase, thus decreasing NO production and increasing reactive oxygen species. We have shown previously that Ang II elevates ARG activity and reduces NO formation in bovine aortic endothelial cells (BAECs). Here we show that Ang II also increases ARG activity in vivo and that activation of p38 MAPK is involved. In aortas from mice given s.c. infusion of Ang II (42 μg/kg/h, 2 wks), ARG activity was elevated compared to controls and was accompanied by impaired EC‐dependent vasorelaxation. Treatment of the mice with the p38 MAPK inhibitor SB 202190 (5 μg/kg/d, s.c.) significantly inhibited the Ang II‐induced increase in ARG activity and improved vasorelaxation. Studies in BAECs exposed to Ang II (0.1 μM, 24h) showed elevated ARG activity/expression (40%) and decreased NO production (25–30%). These effects were prevented by pretreatment with SB 202190 (2 μM) or the Rho kinase inhibitor Y‐27632 (10 μM), which also prevented phosphorylation of p38 MAPK. Collectively, our results indicate involvement of Rho kinase and p38 MAPK in the Ang II signaling pathway for ARG elevation and ED. Inhibiting p38 MAPK might be a beneficial therapeutic target for ED associated with Ang II. Support: NHLBI 70215 and 76146.