TY - JOUR
T1 - PPARγ Links BMP2 and TGFβ1 Pathways in Vascular Smooth Muscle Cells, Regulating Cell Proliferation and Glucose Metabolism
AU - Calvier, Laurent
AU - Chouvarine, Philippe
AU - Legchenko, Ekaterina
AU - Hoffmann, Nadine
AU - Geldner, Jonas
AU - Borchert, Paul
AU - Jonigk, Danny
AU - Mozes, Miklos M.
AU - Hansmann, Georg
N1 - Funding Information:
We thank Christiane Ritter for excellent technical assistance, Drs. Anna Foryst-Ludwig and Mandy Bloch for advice on the ChIP assay, and Dr. Stefan Engeli for providing the Seahorse equipment. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG grant HA4348/2-1 to G.H.), Kinderherzen e.V. (W-H-001-2014 to G.H.), and Stiftung KinderHerz (2511-6-13 to G.H.).
PY - 2017/5/2
Y1 - 2017/5/2
N2 - 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.
AB - 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.
KW - FoxO1
KW - PFKP
KW - PPP1R3G
KW - Smad3
KW - Stat3
KW - miR-130a/301b
KW - miR331-5p
KW - platelet isoform of phosphofructokinase
KW - protein phosphatase 1 regulatory subunit 3G
KW - pulmonary arterial hypertension
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U2 - 10.1016/j.cmet.2017.03.011
DO - 10.1016/j.cmet.2017.03.011
M3 - Article
C2 - 28467929
AN - SCOPUS:85019007167
SN - 1550-4131
VL - 25
SP - 1118-1134.e7
JO - Cell Metabolism
JF - Cell Metabolism
IS - 5
ER -