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

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.

Loss of adipocyte identity through synergistic repression of PPARγ by TGF-β and mechanical stress

“…PPARγ expression was lost early during the adipocyte-myofibroblast transition and the PPARγ agonist rosiglitazone prevented this loss. This is in line with known anti-fibrotic effects of thiazolidinediones (TZDs) 20,25 . We observed that high PPARγ expression in a heterogeneous population of differentiated OP9 cells was correlated with the lack of transcriptional response to the profibrotic cytokine TGF-β.…”

MicroRNA‐130a controls bone marrow mesenchymal stem cell differentiation towards the osteoblastic and adipogenic fate

“…It is well known that Smurf2 can suppress the expression of Runx2 activity, a critical osteoblast‐specific transcription factor, which leads to decreasing in osteoblast formation . Several studies have clearly demonstrated that PPARγ is highly expressed in early stage of adipogenesis and plays a key role in adipocyte formation . We illustrated that miR‐130a promotes osteogenesis of BMSC by eliminating the effect of Smurf2 and acts as a negative regulator of adipogenesis of BMSC by directly targeting PPARγ.…”

“…39,40 Several studies have clearly demonstrated that PPARγ is highly expressed in early stage of adipogenesis and plays a key role in adipocyte formation. 44,45 We illustrated that miR-130a promotes osteogenesis of BMSC by eliminating the effect of Smurf2 and acts as a negative regulator of adipogenesis of BMSC by directly targeting PPARγ. These results indicated that miR-130a post-transcriptionally regulates Smurf2 and PPARγ expression at osteogenic and adipogenic differentiation process.…”

Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

“…For instance, peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to bind STAT3 as well as Smad3 and inhibit TGFβ1-induced phosphorylation and nuclear translocation of both molecules. [199,200]. Treatment of fibroblasts with the PPARγ agonist, rosiglitazone, highlights potential alternative avenues to modulating profibrotic signaling, as it has been shown to significantly attenuate TGFβ1-mediated up-regulation of fibrotic markers Alpha-Actin-2 (ACTA2) and COL1A1 [201].…”