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(Circulation Research. 1997;80:838-844.)
© 1997 American Heart Association, Inc.

Articles

Vascular Thrombin Receptor Regulation in Hypertensive Rats

Quinn Capers, IV, Jørn Bech Laursen, Toshiki Fukui, Sanjay Rajagopalan, Ichiro Mori, Pingping Lou, Bruce A. Freeman, William R. Berrington, Kathy K. Griendling, David G. Harrison, Marschall S. Runge, R. Wayne Alexander, , W. Robert Taylor

From the Departments of Medicine, Divisions of Cardiology, Emory University School of Medicine (Q.C. IV, J.B.L., T.F., S.R., I.M., P.L., K.K.G., D.G.H., R.W.A., W.R.T.) and the Atlanta Veterans Administration Hospital (D.G.H., W.R.T.), Atlanta, Ga; the Department of Anesthesiology (B.A.F., W.R.B.), University of Alabama at Birmingham; the Department of Medicine (M.S.R.), Division of Cardiology, the University of Texas Medical Branch–Galveston; and Medical Department B (J.B.L.), Rigshospitalet, Copenhagen, Denmark.

Correspondence to W. Robert Taylor, MD, PhD, Woodruff Memorial Building, Room 308, Division of Cardiology, 1639 Pierce Dr, Emory University School of Medicine, Atlanta, GA 30322. E-mail wtaylor{at}emory.edu

Abstract Thrombin has been implicated as an important mediator of vascular lesion formation in atherosclerosis and restenosis. To investigate a potential role for thrombin signaling in the vascular response to hypertension, we have studied thrombin receptor (TR) expression and regulation in hypertensive rats. Aortic TR mRNA was upregulated by angiotensin II (Ang II)–induced hypertension (10.7±2.5 times control, P<.02), which correlated with a 4-fold increase in thrombin-induced constriction in isolated endothelium-denuded aortic rings. The AT₁ receptor antagonist losartan normalized blood pressure and TR mRNA. Conversely, lowering blood pressure to the same degree with hydralazine did not abolish the upregulation of TR mRNA expression. When low-renin low–Ang II hypertension was induced in Dahl salt-sensitive rats, there was no detectable increase in the expression of aortic thrombin receptor mRNA. Finally, treatment with a chimeric heparin-binding form of the recombinant human Cu/Zn superoxide dismutase caused complete inhibition of TR mRNA upregulation, suggesting that an increased rate of superoxide anion production is an important signaling mechanism. Thus, increased TR expression via a redox-sensitive mechanism in the aortic smooth muscle of rats treated with Ang II represents a novel in vivo mechanism through which the hypertensive effects of Ang II are mediated.

Key Words: hypertension • aorta • vascular smooth muscle • angiotensin II • Dahl rat

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