P38 MAP kinase pathway regulates angiotensin II-induced contraction of ratvascular smooth muscle

Angiotensin II (ANG II) is a multifunctional hormone that exerts potent vas oconstrictor and hypertrophic effects on vascular smooth muscle. Here, we d emonstrate that the p38 mitogen-activated protein (MAP) kinase pathway is i nvolved in ANG II-induced vascular contraction. Addition of ANG II to rat a ortic smooth muscle cells (SMC) caused a rapid and transient increase of p3 8 activity through activation of the AT(1) receptor subtype. This response to ANG II was strongly attenuated by pretreating cells with antioxidants an d diphenylene iodonium and was mimicked by exposure of cells to H2O2. Stimu lation of p38 by ANG II resulted in the enzymatic activation of MAP kinase- activated protein (MAPKAP) kinase-2 and the phosphorylation of heat shock p rotein 27 (HSP27) in aortic SMC. Pretreatment of cells with the specific p3 8 MAP kinase inhibitor SB-203580 completely blocked the ANG II-dependent ac tivation of MAPKAP kinase-2 and phosphorylation of HSP27. ANG II also cause d a robust activation of MAPKAP kinase-2 in the intact rat aorta. Incubatio n with SB-203580 significantly decreased the potency of ANG II to induce co ntraction of rat aortic rings and depressed the maximal hormone response. T hese results suggest that the p38 MAP kinase pathway selectively modulates the vasoconstrictor action of ANG II in vascular smooth muscle.