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Research ArticleArticle

Dissociation of Angiotensin II-Stimulated Activation of Mitogen-Activated Protein Kinase Kinase from Vascular Contraction

Stephanie W. Watts, Jennifer A. Florian and Kimberly M. Monroe
Journal of Pharmacology and Experimental Therapeutics September 1998, 286 (3) 1431-1438;
Stephanie W. Watts
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Jennifer A. Florian
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Kimberly M. Monroe
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Abstract

Angiotensin II (Ang II) is a potent pressor hormone, a stimulus for vascular smooth muscle hypertrophy and an activator of multiple tyrosine kinases. The physiological effects of Ang II are mediated through activation of AT1 and AT2 receptors, receptors that have been coupled to tyrosine kinase(s) and tyrosine phosphatases, respectively. Agonists of G protein-coupled receptors, of which Ang II is one, have recently been shown to stimulate smooth muscle contraction in part via activation tyrosine kinases. We tested the hypothesis that Ang II-induced contraction in the rat aorta was dependent on activation of tyrosine kinase(s) and specifically investigated the role of the tyrosine kinase mitogen-activated protein kinase kinase (MEK), a kinase important to the mitogen activated protein kinase (MAPK) pathway. Rat thoracic aortic strips denuded of endothelium and cultured aortic smooth muscle cells were used in isolated tissue baths for measurement of isometric contractile force and Western analyses of protein tyrosyl-phosphorylation. Ang II (0.1–100 nM)-induced contraction in the aorta was completely blocked by the AT1 receptor antagonist losartan (1 μM) but unaffected by the AT2receptor antagonist PD123319 (100 nM) or tyrosine phosphatase inhibitor sodium orthovanadate (1 μM), indicating an AT1 receptor mediates aortic contraction to Ang II. Neither the tyrosine kinase inhibitor genistein (5 μM), inactive tyrosine kinase inhibitor daidzein (5 μM) nor MEK inhibitor PD098059 (10 μM) reduced Ang II-induced contraction; the concentrations of inhibitors used maximally reduced contraction stimulated by other agonists of G protein-coupled receptors such as serotonin. Moreover, Ang II-induced contraction was not altered by the combination of PD098059 and PD123319, indicating that it is unlikely AT2 receptor stimulation masks activation of the MAPK pathway through AT1 receptor activation. The nonflavone tyrosine kinase inhibitor tyrphostin B42 (30 μM) reduced Ang II-induced maximal contraction (to 11.2% control) but, unlike the other tyrosine kinase inhibitors, also reduced KCl-induced contraction (to 55.2% control), indicating a probable nonselectivity of tyrphostin B42. Ang IIinduced maximal contraction was reduced by the L-type voltage gated calcium channel antagonist nifedipine (50 nM), consistent with the activation of calcium channels by Ang II. In cultured rat aortic smooth muscle cells, Ang II (0.1–1000 nM) stimulated concentration-dependent tyrosyl-phosphorylation of the extracellular signal regulated kinase (Erk) mitogen activated protein kinases (maximal stimulation, fold basal: Erk-1 = 17-fold, Erk-2 = 3-fold), indicating that Ang II can activate MEK. Losartan (1 μM) abolished Ang II (10 nM)-induced Erk tyrosyl-phosphorylation and PD098059 (10 μM), which did not diminish Ang II-induced aortic contraction, reduced Ang II (10 nM)-stimulated phosphorylation of Erk-2 by 72%. Finally, Ang II (1 μM) increased tyrosyl-phosphorylation of the Erk proteins in isolated aorta exposed to Ang II for 5 min. Thus, while Ang II can stimulate both MEK activation and vascular contraction viainteraction with AT1 receptors, stimulation of MEK does not appear to be important for Ang II-induced contraction. These findings dissociate the process of Ang II-stimulated Erk protein tyrosyl-phosphorylation from Ang II-induced contraction in the rat aorta.

Footnotes

  • Send reprint requests to: Dr. Stephanie W. Watts, B445 Life Sciences Building, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317. E-mail:wattss{at}pilot.msu.edu

  • ↵1 This research was supported by a Grant-in-Aid from the American Heart Association, Michigan Affiliate and and a Scientist Development Training Grant from the American Heart Association National Center.

  • Abbreviations:
    Ang II
    angiotensin II
    Erk
    extracellular signal-regulated kinase
    5-HT
    5-hydroxytryptamine
    MAPK
    mitogen-activated protein kinase
    MEK
    MAPK/Erk kinase
    PD098059
    2-(2′-amino-3′-methoxyphenyl)-oxanaphthalen-4-one
    PD123319
    (S)-(+)-1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid
    PE
    phenylephrine
    SDS
    sodium dodecyl sulfate
    • Received April 21, 1998.
    • Accepted April 29, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 3
1 Sep 1998
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Research ArticleArticle

Dissociation of Angiotensin II-Stimulated Activation of Mitogen-Activated Protein Kinase Kinase from Vascular Contraction

Stephanie W. Watts, Jennifer A. Florian and Kimberly M. Monroe
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1431-1438;

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Research ArticleArticle

Dissociation of Angiotensin II-Stimulated Activation of Mitogen-Activated Protein Kinase Kinase from Vascular Contraction

Stephanie W. Watts, Jennifer A. Florian and Kimberly M. Monroe
Journal of Pharmacology and Experimental Therapeutics September 1, 1998, 286 (3) 1431-1438;
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