Decrease in Tripartite Motif Containing 24 suppresses hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/mammalian target of rapamycin complex 1 pathway

Abstract

ABSTRACT Tripartite Motif Containing 24 (TRIM24) is an oncogenic protein and promotes proliferation in several cancer cell lines. Nevertheless, the role of TRIM24 in proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) remains to be clarified. The current study was aimed to reveal the role of TRIM24 in proliferation and migration of PASMCs during the development of pulmonary arterial hypertension (PAH). In pulmonary arteries (PAs) of chronic hypoxia-PAH (CH-PAH) mice and PASMCs challenged with hypoxia, the expression of TRIM24 was increased. Silencing TRIM24 by Trim24 short hair RNA (shTrim24) suppressed hypoxia-induced increase in Ki-67 positive PASMCs and wound-healing rate. Furthermore, hypoxia caused enhanced phosphorylation of AKT and two major effectors of mammalian target of rapamycin complex 1 (mTORC1), S6 and 4EBP1 in PASMCs. The enhancement was then attenuated after silencing TRIM24. Both restoring mTORC1 activity and AKT reactivation abolished silencing TRIM24-mediated inhibition of proliferation and migration of PASMCs. Additionally, AKT reactivation also reversed the declined phosphorylation of S6 and 4EBP1 induced by shTrim24. In conclusion, TRIM24 is involved in the excessive proliferation and migration of PASMCs after hypoxic stimulus during PAH. The mechanism of TRIM24-mediated regulation of PASMCs is partly illustrated by promoting activity of AKT/mTORC1 signaling pathway.