Researchers demonstrated that glioma-associated oncogene homolog 1 (GLI1) is significantly increased in pulmonary arterial smooth muscle cells (PASMCs) in a rat model of pulmonary arterial hypertension (PAH), as published in the Journal of Molecular and Cellular Cardiology.

They also found that targeting the ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway was effective in preventing the remodeling of the pulmonary vascular system and development of PAH in rats.

“Previous studies have demonstrated that GLI1 regulates the proliferation and differentiation of hematopoietic stem cells and myeloid progenitors, and overexpression of GLI1 promotes the proliferation, migration and invasion of gastric cancer cells and endometrial stromal cells,” they wrote.


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“In the present study, we hypothesize that elevated KLF5 promotes GLI1 expression leading to PASMCs proliferation and migration, thereby contributing to pulmonary vascular remodeling and PAH.”

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The research team cultured primary rat PASMCs and stimulated them with endothelin-1 (ET-1) to promote their proliferation and migration, as occurs in PAH. GLI1 expression was assessed and was significantly upregulated in the ET-1-treated PASMCs, and it triggered their proliferation and migration as well as pulmonary vascular remodeling.

At the same time, the team administered GANT58, a GLI1 inhibitor, to the rat PAH model, resulting in the suppression of pulmonary vascular remodeling and no development of PAH.

A detailed examination of the PAH-related indicators revealed that the ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway is essential to the increase in GLI1 expression in ET-1-treated PASMCs and to the development of pulmonary vascular remodeling and PAH in rats. Furthermore, the authors found transcription factor KLF5 was upregulated by ETAR/miR-27b-3p/FBXW7/KLF5/GLI1, and its inhibition via ML264 reduced pulmonary vascular remodeling and prevented PAH in the rat model.

The authors, therefore, suspect that interfering with the ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 signaling axis might represent a novel treatment approach for the prevention and treatment of PAH.

Reference

Want Q, Chai L, Zhang Q, et al. Induction of GLI1 by miR-27b-3p/FBXW7/KLF5 pathway contributes to pulmonary arterial hypertension. J Mol Cell Cardiol. Published online July 8, 2022. doi:10.1016/j.yjmcc.2022.06.012