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

Abstract

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 g/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 (AT 2 ) expression. In contrast, the decline in BP with angiotensin receptor subtype 1 (AT 1 ) antagonism and vascular AT 1 abundance were unaltered, which indicates a selective effect of CRP on AT 2 . Ex vivo experiments further showed that the CRP-induced decrease in AT 2 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 AT 2 expression without affecting AT 1 . Conclusions-These findings provide direct evidence for CRP-induced hypertension, and they further identify a novel underlying mechanism involving downregulation of AT 2 related to NO deficiency.

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

“…Importantly, Grad et al [9] reported significantly decreased mRNA and protein expression of eNOS following vascular injury in human CRP Tg mice. CRP has also been shown to induce hypertension in CF1 Tg mice expressing rabbit CRP (CF1-CRP) attributable to CRP-induced decline in bioavailable NO [33]. However, the molecular mechanisms for the inhibition of eNOS by CRP have not been elucidated.…”

Inflammatory markers are associated with left ventricular hypertrophy and diastolic dysfunction in a population-based sample of elderly men and women

“…It is possible that CRP could induce direct myocardial effects, as CRP can cause intimal hypertrophy both in vitro and in animal studies. 27,28 Alternatively, such effects may be indirect as studies of transgenic mice have associated CRP with the development of hypertension 29 and perivascular fibrosis. 30 The relationship between CRP genotype and human LVH was investigated for the first time in a study by Mann et al 31 They observed an association between a variant of the CRP gene with exercise-induced LVH in young healthy males, undergoing an identical 12-week physical training program.…”

CRP induces hypertension in animal models: homo sapiens says NO

“…It should be emphasized, however, that unlike the current study and the study by Guan et al, 5 they suggested this effect was not attributable to the effect of theAT-1 receptor, which was unaltered, but to a decrease in the AT-2 receptor. However, the study by Vongpatanasin et al 6 provided little further information with regard to molecular insights.…”

“…They also showed a decreased expression of eNOS and AT-2 receptors. This was accompanied by impairment in endotheliumdependent vasorelaxation.Previously, Vongpatanasin et al 6 reported that CRP induces hypertension in CF1 transgenic mice expressing rabbit CRP (CF1-CRP) under the regulation of the phosphoenolpyruvate carboxykinase promoter, compared with wild-type CF1 control. CRP levels attained were about 10-15 mg l À1 .…”