Abstract 5568: Increased C- Reactive Protein Causes Endothelial Dysfunction and Hypertension in Rats
Several prospective studies have shown that C-reactive protein (CRP) is a predictor of hypertension. These studies are limited by confounding variables, thus a causal linkage between CRP and hypertension is far from clear. Herein, we investigate whether high circulating human CRP levels can induce the development of hypertension in rats. A single intravenous injection of adeno-associated virus (AAV)-hCRP into rats resulted in efficient and sustained hCRP expression and led to elevated blood pressure 2 months after gene transfer that persisted for another 2 months. This effect was associated with decreased nitric oxide (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 1 receptor (AT1), endothelin-1 (ET-1) and endothelin type A receptor (ETA), and decreased expression of angiotensin type 2 receptor (AT2) and endothelial NO synthase (eNOS) in thoracic aortas, and increased arterial stiffness. Ex vivo studies indicated a similar detrimental effect of CRP that was reversed by the NO donor. These data demonstrate that AAV vector-mediated CRP expression resulted in hypertension in rats that was mediated through reduction of NO production and subsequent alteration in ET-1 and renin-angiontensin system activation, furthermore, impaired arterial elasticity may also contribute to CRP-induced hypertension. These results support a causal role for CRP in the pathogenesis of hypertension.