Homo sapiens ChIP-seq (Pulmonary artery)

TGFB1 and BMP2 are functional antagonists of pathological remodeling in the arteries, heart and lung, however, the underlying molecular mechanisms in vascular smooth muscle cells (VSMC) are unclear. We found that TGFB1 activates a novel Stat3-FoxO1 pathway, mitochondrial metabolism and proliferation in human pulmonary artery SMC (HPASMC). TGFB1 decreases PPARG expression, a downstream effector of BMP2, through miRNA-130a/301b. Conversely, PPARG activation inhibits major TGFB1-mediated processes: (1) phosphorylation cascades (Smad3/4 and Stat3-FoxO1) by directly binding to Smad3 and Stat3, (2) energy metabolism (mitochondrial activity, PFKP via miR-331-5p, PPP1R3G), and (3) HPASMC proliferation. PPARG knockdown/deletion in VSMC leads to TGFB1 pathway activation in vitro and in vivo. Mice with heightened circulating TGFB1 develop pulmonary arterial hypertension (PAH), right ventricular hypertrophy, muscularization and loss of peripheral pulmonary arteries, which was fully reversed by PPARG agonist treatment. Hence, PPARG activation may be beneficial in TGFB1-associated diseases, such as PAH, Parenchymal lung disease (Pulmonary fibrosis, Bronchopulmonary dysplasia), heart failure Marfan’s syndrome, and metabolic dysfunction.