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

Laurent Calvier, Philippe Chouvarine, Ekaterina Legchenko, Nadine Hoffmann, Jonas Geldner, Paul Borchert, Danny Jonigk, Miklos M. Mozes, Georg Hansmann

Research output: Contribution to journalArticle

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1118-1134.e7
JournalCell Metabolism
Volume25
Issue number5
DOIs
StatePublished - May 2 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Calvier, L., Chouvarine, P., Legchenko, E., Hoffmann, N., Geldner, J., Borchert, P., Jonigk, D., Mozes, M. M., & Hansmann, G. (2017). PPARγ Links BMP2 and TGFβ1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism. Cell Metabolism, 25(5), 1118-1134.e7. https://doi.org/10.1016/j.cmet.2017.03.011