Adeno-Associated Virus-Mediated Human C-Reactive Protein Gene Delivery Causes Endothelial Dysfunction and Hypertension in Rats

BACKGROUND: Prospective studies have shown that C-reactive protein (CRP) is a predictor of hypertension. Because of confounding variables, a causal linkage between CRP and hypertension has not been clearly shown. We investigated whether high circulating concentrations of human CRP can induce hypertension in rats. METHODS: We administered a single intravenous injection of adeno-associated virus-green fluorescent protein (AAV-GFP) or AAV-hCRP and measured blood pressure. Using ELISA, we measured serum hCRP, serum endothelium I (ET-1), and urine cGMP, and we measured serum nitric oxide (NO) using the Griess method. We recorded heart rate, maximum pressure arterial elastance, mean aortic pressure, cardiac output: and maximum rate of rise in left ventricular pressure (dP/dt max). RESULTS: A single injection of AAV-hCRP resulted in efficient and sustained hCRP expression and led to increased blood pressure 2 months after gene transfer that persisted for another 2 months. This effect was associated with decreased NO production, as demonstrated by decreased serum NO concentration and urinary cGMP excretion, and impairment of endothelial-dependent vascular relaxation. CRP transduction also increased expression of angiotensin type I receptor, ET-1, and endothelin type A receptor, decreased expression of angiotensin type 2 receptor and endothelial NO synthase in thoracic aortas, and increased arterial stiffness. Ex vivo studies indicated a similar detrimental effect of CRP that was reversed by the NO donor. CONCLUSION: A-AV vector-mediated CRP expression resulted in hypertension mediated through reduced NO production and subsequent alteration in ET-1 and renin-angiotensin system activation. Impaired arterial elasticity may also contribute to CRP-induced hypertension. These results support a causal role for CRP in the pathogenesis of hypertension. (C) 2008 American Association for Clinical Chemistry