Abstract 1103: C-Reactive Protein Causes Downregulation of Vascular AT2 Receptor Expression and Systolic Hypertension in Mice
Circulating levels of C-reactive protein (CRP) are an independent predictor of the risk of hypertension. However, it is unknown whether CRP causes blood pressure (BP) elevation. To determine the role of CRP in BP modulation, we measured conscious BP by radiotelemetry in wildtype CF-1 control and CF-1 transgenic mice expressing CRP (CF-1-CRP) under the regulation of the phosphoenolpyruvate carboxykinase promoter. On a standard diet yielding CRP of 45±3 mcg/ml in CF-1-CRP and < 1 mcg/ml in CF-1, systolic BP (SBP) and pulse pressure were higher in CF-1-CRP versus CF-1 (142±5 vs 121±1 mmHg, p<0.01, and 36±3 vs 24±2 mmHg, p<0.05, respectively). In contrast, diastolic BP and heart rate were similar. In CF-1-CRP, SBP fell from 142±5 to 130±1 mmHg (p<0.05) when CRP was lowered from 45±3 to 19±1 mcg/ml by changing to a carbohydrate (CHO)-rich diet, and rose back to 141±3 mmHg with a CHO-free diet yielding CRP of 123±15 mcg/ml in the same mice. Diet changes in CF-1 had no effect on BP. Hemizygous CF-1-CRP mice (hemiCF-1-CRP) on CHO-rich diet yielding lower CRP levels of 9±4 mcg/ml also had higher SBP (130±3 mmHg) than CF-1 (124±1 mmHg, p<0.01). In addition, hemiCF-1-CRP had exaggerated BP elevation with angiotensin II infusion but no difference in BP elevation with norepinephrine or in BP decline with angiotensin receptor subtype 1 (AT1) antagonism with Telmisartan. Whereas AT1 mRNA and protein abundance were similar in aortas of hemiCF-1-CRP and CF-1, AT2 mRNA and protein abundance were decreased by 98% and 48%, respectively, in hemiCF-1-CRP (p<0.05). Ex vivo incubation of aortas from CF-1 mice with CRP similarly reduced AT2 abundance by 50% without affecting AT1. To test the possible role of CRP antagonism of endothelial nitric oxide (NO) synthase, aortas were concomitantly incubated with CRP and the NO donor S-nitroso-N-acetylpenicillamine (SNAP), and SNAP prevented the reduction in AT2. Furthermore, nitro-L-arginine methyl ester administraton to CF-1 mice duplicated the in vivo effect of CRP and caused a loss of vascular AT2 without altering AT1. Thus, CRP causes systolic hypertension in mice, which is related to downregulation of vascular AT2, that may be due to a CRP-induced decline in bioavailable NO.