PPARγ Links BMP2 and TGFβ1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism

  • Cell Metab. 2017 May 2;25(5):1118-1134.e7. doi: 10.1016/j.cmet.2017.03.011.
Laurent Calvier  1 ,  Philippe Chouvarine  1 ,  Ekaterina Legchenko  1 ,  Nadine Hoffmann  1 ,  Jonas Geldner  1 ,  Paul Borchert  1 ,  Danny Jonigk  2 ,  Miklos M Mozes  3 ,  Georg Hansmann  4
Affiliations
  • 1. Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover 30625, Germany.
  • 2. Institute of Pathology, Hannover Medical School, Hannover 30625, Germany.
  • 3. Department of Pathophysiology, Semmelweis University, Budapest 1089, Hungary.
  • 4. Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Hannover 30625, Germany. Electronic address: [email protected].
PMID: 28467929 DOI: 10.1016/j.cmet.2017.03.011
Abstract

BMP2 and TGFβ1 are functional antagonists of pathological remodeling in the arteries, heart, and lung; however, the mechanisms in VSMCs, and their disturbance in pulmonary arterial hypertension (PAH), are unclear. We found a pro-proliferative TGFβ1-Stat3-FoxO1 axis in VSMCs, and PPARγ as inhibitory regulator of TGFβ1-Stat3-FoxO1 and TGFβ1-Smad3/4, by physically interacting with STAT3 and SMAD3. TGFβ1 induces fibrosis-related genes and miR-130a/301b, suppressing PPARγ. Conversely, PPARγ inhibits TGFβ1-induced mitochondrial activation and VSMC proliferation, and regulates two glucose metabolism-related Enzymes, platelet isoform of phosphofructokinase (PFKP, a PPARγ target, via miR-331-5p) and protein Phosphatase 1 regulatory subunit 3G (PPP1R3G, a SMAD3 target). PPARγ knockdown/deletion in VSMCs activates TGFβ1 signaling. The PPARγ Agonist pioglitazone reverses PAH and inhibits the TGFβ1-Stat3-FoxO1 axis in TGFβ1-overexpressing mice. We identified PPARγ as a missing link between BMP2 and TGFβ1 pathways in VSMCs. PPARγ activation can be beneficial in TGFβ1-associated diseases, such as PAH, parenchymal lung diseases, and Marfan's syndrome.

Keywords
FoxO1; PFKP; PPP1R3G; Smad3; Stat3; miR-130a/301b; miR331-5p; platelet isoform of phosphofructokinase; protein phosphatase 1 regulatory subunit 3G; pulmonary arterial hypertension.