title: Peroxisome proliferator-activated receptor-γ mutations responsible for lipodystrophy with severe hypertension activate the cellular renin-angiotensin system.
abstract: OBJECTIVE
  Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular renin-angiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ. Approach and Results- We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, 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 PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ 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 PPARγ. 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. PPARγ 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.
authors: INSERM UMRS938, Centre de Recherche Saint Antoine, Paris, France.
authors: Martine
authors: M
authors: Auclair
authors: Corinne
authors: C
authors: Vigouroux
authors: Franck
authors: F
authors: Boccara
authors: Emilie
authors: E
authors: Capel
authors: Catherine
authors: C
authors: Vigeral
authors: Bruno
authors: B
authors: Guerci
authors: Olivier
authors: O
authors: Lascols
authors: Jacqueline
authors: J
authors: Capeau
authors: Martine
authors: M
authors: Caron-Debarle
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D016022:Case-Control Studies; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D052496:Lipodystrophy, Familial Partial / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018384:Oxidative Stress; D047495:PPAR gamma / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics; D000077154:Rosiglitazone; D012720:Severity of Illness Index; D012867:Skin / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection; D055815:Young Adult
chemical_list: C457499:2-chloro-5-nitrobenzanilide; C544065:AGTR1 protein, human; D000813:Anilides; D018836:Inflammation Mediators; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases