Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 171, Issue -, Pages 16-29Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.06.012
Keywords
GLI1; miR-27b-3p; FBXW7; KLF5; Pulmonary arterial hypertension
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Funding
- National Natural Science Foundation of China [81670051, 81970050, 81800052]
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GLI1 plays a role in promoting proliferation and migration of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH) through the miR-27b-3p/FBXW7/KLF5/GLI1 pathway. Targeting this signaling axis may have potential value in preventing and treating PAH.
Glioma-associated oncogene homolog 1 (GLI1), a zinc-finger transcription factor, is upregulated in tumors and promotes cancer cell proliferation and migration. However, whether GLI1 involves in pulmonary artery smooth muscle cells (PASMCs) proliferation and migration and the detailed molecular mechanisms underlying GLI1 in pulmonary arterial hypertension (PAH) are not yet clear. Primary cultured rat PASMCs and monocrotaline (MCT)-induced PAH rats model were applied to address these issues in the present study. We found that the expression of GLI1 was significantly increased in endothelin-1 (ET-1) treated PASMCs, accompanied with the activation of microRNA (miR)-27b-3p/F-box and WD repeat domain containing 7 (FBXW7)/kruppel-like factor 5 (KLF5)/GLI1 pathway through endothelin-1 receptor type A (ETAR). Elevated miR-27b-3p suppressed FBXW7 expression, which led to KLF5 accumulation by decreasing its ubiquitinated degradation, KLF5 further induced GLI1 upregulation leading to PASMCs proliferation and migration. In addition, in MCT-induced PAH rats, targeting ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway effectively prevented the pulmonary vascular remodeling and the development of PAH in rats. Our study indicates that interfering ETAR/miR-27b-3p/FBXW7/KLF5/ GLI1 signaling axis might have a potential value in the prevention and treatment of PAH.
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