PPARγ is a gatekeeper for extracellular matrix and vascular cell homeostasis: Beneficial role in pulmonary hypertension and renal/cardiac/pulmonary fibrosis

Gábor Kökény, Laurent Calvier, Ekaterina Legchenko, Philippe Chouvarine, Miklós M. Mózes, Georg Hansmann

Research output: Contribution to journalReview article

5 Scopus citations

Abstract

Purpose of reviewPulmonary 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 findingsIndependent 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.SummaryPharmacological 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.

Original languageEnglish (US)
Pages (from-to)171-179
Number of pages9
JournalCurrent opinion in nephrology and hypertension
Volume29
Issue number2
DOIs
StatePublished - Mar 1 2020

Keywords

  • Fibrosis
  • Inflammation
  • Peroxisome proliferator-activated receptor gamma
  • Pioglitazone
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Internal Medicine
  • Nephrology

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