Published Online
on February 5, 2007

A more recent version of this article appeared on February 27, 2007

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Submitted on September 14, 2006
Accepted on January 5, 2007

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, and 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.).

^* To whom correspondence should be addressed. E-mail: philip.shaul{at}utsouthwestern.edu.

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.

Key words: angiotensin • C-reactive protein • endothelium • hypertension • nitric oxide • receptors

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