PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis.
Mózes, Miklós M
Current opinion in nephrology and hypertension
MetadataShow full item record
Kökény, G., Calvier, L., Legchenko, E., Chouvarine, P., Mózes, M. M., & Hansmann, G. (2020). PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis.. Current opinion in nephrology and hypertension, 29 (2), 171-179. https://doi.org/10.1097/mnh.0000000000000580
PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and apoptosis, pulmonary arterial smooth muscle cell (PASMC) proliferation, inflammation, vasoconstriction, and metabolic disturbances that include disrupted bone morphogenetic protein receptor (BMPR2)-peroxisome proliferator-activated receptor gamma (PPARγ) axis and DNA damage. Activation of PPARγ improves many of these mechanisms, although erroneous reports on potential adverse effects of thiazolidinedione (TZD)-class PPARγ agonists reduced their clinical use in the past decade. Here, we review recent findings in heart, lung, and kidney research related to the pathobiology of vascular remodeling and tissue fibrosis, and also potential therapeutic effects of the PPARγ agonist pioglitazone. RECENT FINDINGS: Independent of its metabolic effects (improved insulin sensitivity and fatty acid handling), PPARγ activation rescues BMPR2 dysfunction, inhibits TGFβ/Smad3/CTGF and TGFβ/pSTAT3/pFoxO1 pathways, and induces the PPARγ/apoE axis, inhibiting vascular remodeling. PPARγ activation dampens mtDNA damage via PPARγ/UBR5/ATM pathway, improves function of endothelial progenitor cells (EPCs), and decrease renal fibrosis by repressing TGFβ/pSTAT3 and TGFβ/EGR1. SUMMARY: Pharmacological PPARγ activation improves many hallmarks of PAH, including dysfunction of BMPR2-PPARγ axis, PAEC, PASMC, EPC, mitochondria/metabolism, and inflammation. Recent randomized controlled trials, including IRIS (Insulin Resistance Intervention After Stroke Trial), emphasize the beneficial effects of PPARγ agonists in PAH patients, leading to recent revival for clinical use.
Muscle, Smooth, Vascular, Myocardium, Kidney, Extracellular Matrix, Myocytes, Smooth Muscle, Animals, Humans, Hypertension, Pulmonary, Pulmonary Fibrosis, DNA Damage, Fibrosis, PPAR gamma, Homeostasis, Bone Morphogenetic Protein Receptors, Type II, Transforming Growth Factor beta1
Embargo Lift Date
External DOI: https://doi.org/10.1097/mnh.0000000000000580
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299988
All rights reserved