Abstract MP40: Hiv Impairs Endothelial Function And Elevates Blood Pressure Via Tnfa Dependent Mechanisms In Male And Female Mice.

Abstract

HIV is a major health concern with over 37 million individuals worldwide living with HIV. The onset of combination antiretroviral therapy (cART) patients with HIV (PWH) live longer but exhibit accelerated development of cardiovascular disease. Clinical evidence indicates that 35% of PWH exhibit hypertension, however, the etiopathology is still ill-defined. We plan to take advantage of a transgenic mouse model (Tg26) that mimics patients with a repressed virus, to test the hypothesis that viral infection independent of cART induces endothelial dysfunction and hypertension via a TNF-α mediated mechanism. Vascular reactivity was analyzed via wire myography and blood pressure (BP) recorded via radio-telemetry. Results showed that viral infection impaired aorta endothelium-dependent relaxation as reflected by a decrease in acetylcholine-mediated relaxation in both Tg26 mice (P<0.05) which was ameliorated with the NOX 1/4 inhibitor GKT 137831. Smooth muscle cell-dependent relaxation (SNP) and contractility to phenylephrine and KCl remained intact in Tg26 mice. Viral infection increased systolic, diastolic, and mean arterial pressure (MAP: male: WT=112.3±1.3 vs Tg26=121.9±4.0 mmHg/ female: WT=110.6±3.01/ Tg26=120.3±6.9 mmHg) and elevated heart rate (HR) in both sexes (p<0.05). We used atropine, propranolol, and hexamethonium in WT and Tg26 mice to investigate the contribution of the autonomic nervous system to hypertension. HR responses to both atropine (Female: +5.07±2.8% vs. male +4.3±5.4% of baseline) and propranolol (Female: 19.9±6.1% vs. male 12.0±4.3%) revealed no significance or sex differences in WT mice and no effects of viral infection on autonomic control of heart rate in Tg26 mice. BP responses to hexamethonium revealed no effect of sex or viral infection, supporting a limited contribution of the autonomic nervous system to hypertension in Tg26 mice. However, we found that TNFα inhibition with etanercept reduced mean arterial pressure in Tg26 mice to the level of the WT mice (WT=112.3±1.3, Treated=110.1±0.185) and improved endothelial function. These data indicate that HIV infection contributes to cardiovascular disease via inducing endothelial dysfunction and hypertension via NOX and TNFα-dependent mechanisms respectively.