Overexpression of Krüppel-Like Factor 4 (KLF4) Inhibits the Proliferation of Pulmonary Arterial Smooth Muscle Cells Through ERK1/2 Signaling Under Hypoxia Environment

Abstract Background This study is designed to examine the role of Krüppel-like factor 4 in mediating the proliferation of pulmonary artery smooth muscle cells (PASMCs) in hypoxic pulmonary hypertension and the underlying mechanisms. Methods Experiments were conducted using PASMCs isolated from male Sprague-Dawley rats. The cells were divided into 24 h group, 48 h group and 72 h group according to different hypoxia treatment time. For specific inhibition of the ERK1/2 and p38 signaling pathways, PASMCs were treated with the ERK1/2-specific inhibitor. KLF4 was cloned from plasmid into the eukaryotic expression vector and transfected into PASMCs for KLF4 overexpression and was transfected into PASMCs for KLF4 knockdown. Results PASMCs dedifferentiation and proliferation phenotypes under hypoxia conditioned culture were not synchronous. Overexpression of KLF4 attenuated extracellular signal-regulated kinase (ERK)1/2-mediated proliferative signals in PASMCs. Knockdown of KLF4 expression resulted in increased ERK1/2 phosphorylation and significantly increased hypoxia-induced PASMCs proliferation, while p38 did not change and showed no influence on proliferation during the above process. Conclusions Our results indicate for the first time that KLF4 plays inhibitor role through activating ERK1/2 in PASMCs proliferation under hypoxia condition, expanding existing reports on the participation of KLF4 in the development of HPH. Our findings may provide pharmacological targets for therapy of HPH.