p38 MAP kinase pathway regulates angiotensin II-induced contraction of rat vascular smooth muscle.
Angiotensin II (ANG II) is a multifunctional hormone that exerts potent vasoconstrictor and hypertrophic effects on vascular smooth muscle. Here, we demonstrate that the p38 mitogen-activated protein (MAP) kinase pathway is involved in ANG II-induced vascular contraction. Addition of ANG II to rat aortic smooth muscle cells (SMC) caused a rapid and transient increase of p38 activity through activation of the AT(1) receptor subtype. This response to ANG II was strongly attenuated by pretreating cells with antioxidants and diphenylene iodonium and was mimicked by exposure of cells to H(2)O(2). Stimulation of p38 by ANG II resulted in the enzymatic activation of MAP kinase-activated protein (MAPKAP) kinase-2 and the phosphorylation of heat shock protein 27 (HSP27) in aortic SMC. Pretreatment of cells with the specific p38 MAP kinase inhibitor SB-203580 completely blocked the ANG II-dependent activation of MAPKAP kinase-2 and phosphorylation of HSP27. ANG II also caused a robust activation of MAPKAP kinase-2 in the intact rat aorta. Incubation with SB-203580 significantly decreased the potency of ANG II to induce contraction of rat aortic rings and depressed the maximal hormone response. These results suggest that the p38 MAP kinase pathway selectively modulates the vasoconstrictor action of ANG II in vascular smooth muscle.
Centre de Recherche, Centre Hospitalier de l'Université de Montréal, and Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada H2W 1T8. meloches@ere.umontreal.ca
S
S
Meloche
J
J
Landry
J
J
Huot
F
F
Houle
F
F
Marceau
E
E
Giasson
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D001013:Aorta, Thoracic / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D000804:Angiotensin II; D002118:Calcium; D004533:Egtazic Acid; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C486114:Hspb1 protein, rat; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C093642:SB 203580