Cited2 inhibited hypoxia-induced proliferation and migration of PASMCs via the TGF-β1/Cited2/PPARγ pathway

Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) contribute to hypoxia-induced pulmonary hypertension (HPH). The transcription factor Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (Cited2) has been implicated in the control of tumor cells and mesenchymal stem cell (MSC) and cardiomyocyte growth or migration. Whether Cited2 is involved in the proliferation and migration of PASMCs and the underlying mechanisms deserve to be explored.  Cited2 expression was detected in rat PASMCs under hypoxia conditions and HPH rat models. The effect of Cited2 on the proliferation and migration of PASMC was detected by overexpression or knockdown of the Cited2 gene. After PAMSCs were treated with recombinant TGF-β1 and the lentivirus vector overexpressing Cited2, expression of peroxisome proliferator-activated receptor gamma (PPARγ) was examined by western blotting. We revealed that hypoxia down-regulated the expression of Cited2 in PASMCs and rat pulmonary arteries. Cited2 overexpression inhibited the proliferation and migration of PASMCs under hypoxia, while Cited2 knockdown induced the proliferation and migration of PASMCs. Cited2 inhibits the negative regulation of the TGF-β1 pathway on PPARγ to inhibit the proliferation and migration of PASMCs. These findings suggest that increased Cited2 expression contributes to the inhibition of PASMCs proliferation and migration by regulating TGF-β1-mediated target gene expression in HPH and provides a new target for molecular therapy of HPH.