Krüppel-like Factor 7 inhibits proliferation and migration of pulmonary smooth muscle cells via p21 activation

The aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are critical contributors to the pulmonary vascular remodeling that occurs during the development of Pulmonary arterial hypertension (PAH). Krüppel-like Factor 7 (KLF7) has been reported to be involved in the development of certain cardiovascular diseases. However, the role of KLF7 in PAH remains unknown. Here, we aimed to explore whether KLF7 mediates the proliferation and migration of PASMCs and its underlying mechanism. In this study, Sprague Dawley rats were exposed to 60 mg/kg monocrotaline (MCT) for 3 weeks to induce PAH and human PASMCs were stimulated with 20 ng/ml platelet-derived growth factor-BB (PDGF-BB) for 24 h to induce proliferation and migration. The mRNA and protein expression of KLF7 were significantly down-regulated in MCT-induced PAH rats and PDGF-BB-treated PASMCs. Under normal conditions, KLF7 knockdown obviously promoted PASMCs proliferation and migration, whereas KLF7 overexpression exhibited the opposite effects. Furthermore, PDGF-BB promoted the PASMCs proliferation and migration, increased the cell proportion in S phase, which was significantly attenuated by overexpression of KLF7. Mechanistic investigation indicated that KLF7 through activation its target protein, the cell cycle inhibitor p21, which finally leading to the inhibition of PASMCs growth. Consistently, UC2288, a specific inhibitor of p21, partially reversed the PASMCs proliferation inhibited by KLF7 overexpression. Taken collectively, the data suggested that KLF7 inhibits PASMCs proliferation and migration via p21 pathway and it may be used as a new therapeutic target for the PAH.