Lipodystrophy is a congenital disorder or a condition acquired later in life, which can be caused by antiretroviral therapies (ART). Lipodystrophy is characterized by a total or partial absence of adipose tissue resulting in drastic reductions in leptin levels, metabolic disorders and cardiovascular disease (CVD). However the molecular mechanisms whereby lipodystrophy causes CVD are still unclear. In addition, although the FDA recently approved the use of leptin as a therapy to minimize the metabolic dysfunction in lipodystrophic patients, whether leptin replacement therapy improves lipodystrophy-associated CVD remains unknown. The goal of the present application is to combine the use of genetically engineered animal models and pharmacological approaches with cell cultures to identify the molecular mechanism whereby lipodystrophy induces endothelial dysfunction and determine whether leptin treatment restores lipodystrophy associated endothelial dysfunction. Preliminary data for this application report that reduction in adipose mass and leptin levels in mouse models of congenital and ART-induced lipodystrophy is associated with impaired endothelium-dependent relaxation. Furthermore, we show that lipodystrophy increases vascular oxidative stress, elevates endothelial Nox1 expression in the vasculature, reduces vascular peroxisome proliferator-activated receptor gamma (PPAR?) and promotes vascular inflammation characterized by elevated RANTES/CCR5, IL-1?, MCP-1, F4/80, and GATA-3 levels. We also show that ROS scavenging with tempol or the Nox1/Nox4 inhibitor restores endothelial function and Nox1 lack prevents lipodystrophy-induced endothelial dysfunction and vascular inflammation. Moreover, we find that leptin supplementation, restores endothelial function, increases PPAR?, reduces Nox1 in aortae and freshly isolated endothelial cells, reduces RANTES/CCR5 expression and reverts vascular inflammation. Finally, we report that increasing leptin sensitivity in endothelial cells specifically prevents lipodystrophy-induced endothelial dysfunction and vascular inflammation. Based on these findings, we hypothesized that the reduction in endothelial leptin signaling impairs endothelium-dependent relaxation and promotes vascular inflammation via Nox1 dependent mechanisms, in lipodystrophy. This hypothesis will be tested with the three following aims: K99:
Aim 1 : lipodystrophy triggers endothelial dysfunction via Nox1-mediated, PPAR?-dependent mechanisms. K99/R00:
Aim 2 : reduction in endothelial leptin signaling impairs endothelial function in mouse models of lipodystrophy. R00:
Aim 3 : leptin reduces vascular immune cell infiltration via decreasing endothelial RANTES/CCR5 expression.
Metabolic and vascular complications are the most common and life-threatening complications of congenital or acquired forms of lipodystrophy, which are commonly induced by the antiretroviral therapy used to treat HIV- infected patients. The proposed study will combine the use of cultured endothelial cells with genetically engineered animal models and pharmacological approaches to analyze the molecular mechanisms by which lipodystrophy triggers vascular damage and investigate whether leptin supplementation, the current therapeutic strategy for the metabolic dysfunction associated with congenital lipodystrophy, restores vascular function. This study will offer novel therapeutic targets that have the potential of improving the quality of life of patients with lipodystrophy.
