Abstract

Although extremely efficient at suppressing HIV replication, highly active antiretroviral therapy (HAART) induces lipodystrophy, a metabolic disorder characterized by an abnormal adipose tissue distribution, reduced leptin levels and vascular dysfunction. Leptin replacement therapy (LRT) is currently used to improve metabolic function in patients suffering from congenital lipodystrophy. Here, we analyzed whether LRT restores vascular function and inflammation in mice treated with the antiretroviral agent, ritonavir (Rit). Four weeks of Rit reduced body weight [control (C): 28.4±0.5 vs. Rit: 24.4±0.2g*, *P<0.05] and fat mass (C: 10±1 vs. Rit: 6.5±1 %*) confirming that it induces lipodystrophy. Rit impaired aortic endothelial function [Relaxation to acetylcholine: C: 74±4 vs. Rit: 21±15%*), increased ROS producing enzymes (NOX1 and NOXA1), induced vascular inflammation (increased IL-1β, MCP-1, GATA Binding Protein 3 and INF-γ gene expression) and increased TBARS levels. ROS scavenging via tempol or GKT137117, (Nox1/4 inhibitor) pre-incubation blunted endothelial dysfunction. LRT (10μg/day/7 days, osmotic mini-pump), at the end of the 3-week Rit, restored endothelial function, reduced Nox1 and NOXA1 gene expression and vascular inflammation. NOX1 deficiency in Nox1 KO mice protected mice from Rit-induced endothelial dysfunction and vascular inflammation. Increasing endothelial leptin sensitivity via specific deletion of protein tyrosine phosphatase 1B (Ptp1b) in endothelial cells ( Ptp1b-/-EC mice) protected mice from Rit-induced endothelial dysfunction and reduced Nox1 and NOXA1 gene expression, and vascular inflammation. To address the relevance of these observations to other forms of acquired lipodystrophy, experiments were repeated in mice in which lipodystrophy was induced at 8 week of age, by the deletion of Bscl2, a gene involved in adipocyte maturation. Bscl2 deletion reduced fat mass, and induced endothelial dysfunction via ROS-mediated mechanisms. Again, LRT reverted endothelial dysfunction by downregulating Nox1 expression. All together, these data presents leptin as a key regulator of endothelial oxidative stress level and as a potential avenue for the treatment vascular disease.

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