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(Circulation. 2007;115:1020-1028.)
© 2007 American Heart Association, Inc.

Hypertension

C-Reactive Protein Causes Downregulation of Vascular Angiotensin Subtype 2 Receptors and Systolic Hypertension in Mice

Wanpen Vongpatanasin, MD; Gail D. Thomas, PhD; Randall Schwartz, MD; Lisa A. Cassis, PhD; Sherri Osborne-Lawrence, MS; Lisa Hahner, BS; Linda L. Gibson, BS; Steven Black, PhD; David Samols, PhD; Philip W. Shaul, MD

From the Departments of Internal Medicine (W.V., G.D.T.) and Pediatrics (R.S., S.O.-L., L.H., L.L.G., P.W.S.) and the Donald W. Reynolds Cardiovascular Clinical Research Center (W.V., P.W.S.), University of Texas Southwestern Medical Center, Dallas; Graduate Center for Nutritional Sciences, University of Kentucky, Lexington (L.A.C.); and Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio (S.B., D.S.).

Correspondence to Philip W. Shaul, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail philip.shaul{at}utsouthwestern.edu

Received September 14, 2006; accepted January 5, 2007.

Background— Chronic elevations in circulating C-reactive protein (CRP) are associated with a greater risk of hypertension. Whether elevations in CRP cause hypertension is unknown.

Methods and Results— Chronic, conscious blood pressure (BP) measurements were performed by radiotelemetry in wild-type CF1 control and CF1 transgenic mice expressing rabbit CRP (CF1-CRP) under the regulation of the phosphoenolpyruvate carboxykinase promoter. Compared with controls, CF1-CRP mice had hypertension that was predominantly systolic, and the severity of hypertension varied in parallel with changes in CRP levels modulated by dietary manipulation. Mice that were hemizygous for the transgene with CRP levels of 9 µg/mL were also hypertensive, indicating that modest elevations in CRP are sufficient to alter BP. CRP transgenic mice had exaggerated BP elevation in response to angiotensin II and a reduction in vascular angiotensin receptor subtype 2 (AT₂) expression. In contrast, the decline in BP with angiotensin receptor subtype 1 (AT₁) antagonism and vascular AT₁ abundance were unaltered, which indicates a selective effect of CRP on AT₂. Ex vivo experiments further showed that the CRP-induced decrease in AT₂ is a direct effect on the vascular wall, not requiring systemic responses, and that it is reversed by an NO donor, which indicates a role for NO deficiency in the process. In parallel, the chronic inhibition of NO synthase in wild-type mice attenuated vascular AT₂ expression without affecting AT₁.

Conclusions— These findings provide direct evidence for CRP-induced hypertension, and they further identify a novel underlying mechanism involving downregulation of AT₂ related to NO deficiency.

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