Abstract 17112: Transgenic Endothelial-Specific HIV-Nef Expression Induces Pulmonary Hypertension and Systemic Vascular Dysfunction, Which Can Be Reverted by Treatment With Statin

Abstract

Introduction: HIV patients on ART perplexingly remain at higher risk for developing cardiovascular diseases including acute peripheral arterial disease and pulmonary hypertension. A likely culprit for observed vascular changes is HIV protein Nef, detected both intracellularly and extracellularly in the absence of HIV RNA or DNA. Nef is known to induce endothelial dysfunction through the activation of NADPH; statins are known to inhibit NADPH activation. Hypothesis: Nef expression in endothelial cells will trigger cardiopulmonary and vascular pathology; Nef effects will be reversed by statin. Methods: Endothelial-specific expression of HIV-Nef was achieved by mating the VE-Cadherin-Tet off mice with TRE-Nef mice. The resulting Nef+ double transgenics and their Nef- negative littermates were maintained without doxycycline to induce Nef expression. Changes in pulmonary acceleration and ejection times were analyzed by ultrasound (INVEVO2100). Additionally, we assessed the ability of bradykinin-preconstricted aortic rings to dilate in response to acetylcholine in NO-dependent manner. Results: Between week 10 and week 13 of age, Nef expressing mice displayed gradual reduction of PAT/PET ratio (down to the 75% of the original PAT/PET ratio at week 10), indicative of developing pulmonary hypertension (N=6). PAT/PET ratio in Nef-negative mice did not change significantly between week 10 and 13 of age. Importantly, statin treatment initiated at week 10 completely suppressed PAT/PET changes developing in Nef-expressing mice. Arterial rings from Nef expressing mice (n=4) showed significantly impaired dilatation in response to acetylcholine (10% relaxation in Nef+ mice vs 40% relaxation in Nef-negative littermates, p=0.03), indicative of changes in systemic circulation. This difference was significantly attenuated in Nef+ mice receiving statin treatment. Conclusions: Our data suggests that mice with endothelial expression of HIV-Nef display pathological changes in pulmonary and systemic circulation. Statin treatment significantly attenuates changes in parameters indicative of pulmonary and systemic hypertension, suggesting that statin will be beneficial for patients with HIV-induced cardiopulmonary and vascular diseases.