ArticleArteriosclerosis, thrombosis, and vascular biology2013
Peroxisome proliferator-activated receptor-γ mutations responsible for lipodystrophy with severe hypertension activate the cellular renin-angiotensin system.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 59 citations in OpenAlex.
- Clinical Spectrum ofCells · 2023Pooled it
- Structural determinants of non-covalent PPARγ inverse agonism and their therapeutic implications.Nature communications · 2025Article
- Clinical Guidance for Lipodystrophy Syndromes: From Diagnosis and Work-Up to Treatment.Current diabetes reports · 2025Review
- PVAT adipocyte: energizing, modulating, and structuring vascular function during normotensive and hypertensive states.American journal of physiology. Heart and circulatory physiology · 2025Review
- Peroxisome proliferator-activated receptor gamma mutation in familial partial lipodystrophy type three: A case report and review of literature.World journal of diabetes · 2024Article
- Lipodystrophic Laminopathies: From Dunnigan Disease to Progeroid Syndromes.International journal of molecular sciences · 2024Review
- PPARγ Agonist Rosiglitazone and Antagonist GW9662: Antihypertensive Effects on Chronic Intermittent Hypoxia-Induced Hypertension in Rats.Journal of cardiovascular translational research · 2024Article
- The 2023 Walter B. Cannon Award Lecture: Mechanisms Regulating Vascular Function and Blood Pressure by the PPARγ-RhoBTB1-CUL3 Pathway.Function (Oxford, England) · 2024Review
- Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features.Frontiers in endocrinology · 2024Review
- Structure and Function of RhoBTB1 Required for Substrate Specificity and Cullin-3 Ubiquitination.Function (Oxford, England) · 2023Article
- Review article: vascular effects of PPARs in the context of NASH.Alimentary pharmacology & therapeutics · 2022Review
- Isoform-specific functions of PPARγ in gene regulation and metabolism.Genes & development · 2022Article
- Aryl Hydrocarbon Receptor Mechanisms Affecting Chronic Kidney Disease.Frontiers in pharmacology · 2022Review
- Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy.International journal of molecular sciences · 2021Article
- Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin.International journal of molecular sciences · 2021Article
- Role of the Peroxisome Proliferator Activated Receptors in Hypertension.Circulation research · 2021Review
- Molecular and Cellular Bases of Lipodystrophy Syndromes.Frontiers in endocrinology · 2021Review
- Peroxisome proliferator-activated receptor gamma-ligand-binding domain mutations associated with familial partial lipodystrophy type 3 disrupt human trophoblast fusion and fibroblast migration.Journal of cellular and molecular medicine · 2020Article
- PPARγ and RhoBTB1 in hypertension.Current opinion in nephrology and hypertension · 2020Review
- RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity.The Journal of clinical investigation · 2019Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveInactivating 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.
conclusionsTwo 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.
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