Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin-Angiotensin System

Objective-Inactivating peroxisome proliferator-activated receptor-gamma (PPAR gamma) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPAR gamma can repress the vascular reninangiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPAR gamma inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPAR gamma. Approach and Results-We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPAR., respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPAR gamma and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPAR gamma and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPAR gamma. Angiotensin II-mediated mitogen-activated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPAR gamma activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes. Conclusions-Two novel FPLD3-linked PPARG mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension. (Arterioscler Thromb Vasc Biol. 2013; 33: 829-838.)