Induction of GLI1 by miR-27b-3p/FBXW7/KLF5 pathway contributes to pulmonary arterial hypertension.

Abstract

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.

• Authors: Qingting Wang, Limin Chai, Qianqian Zhang, Jian Wang, Jin Liu, Huan Chen, Yan Wang, Yuqian Chen, Nirui Shen, Xinming Xie, Manxiang Li
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 171 Pg. 16-29 (10 2022) ISSN: 1095-8584 [Electronic] England
• PMID: 35810662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Endothelin-1
• F-Box-WD Repeat-Containing Protein 7
• Gli1 protein, rat
• Klf5 protein, rat
• Kruppel-Like Transcription Factors
• MIRN27 microRNA, rat
• MicroRNAs
• Receptor, Endothelin A
• Zinc Finger Protein GLI1
• Monocrotaline

Topics

• Animals
• Cell Proliferation
• Endothelin-1 (metabolism)
• F-Box-WD Repeat-Containing Protein 7 (metabolism)
• Kruppel-Like Transcription Factors (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Monocrotaline
• Myocytes, Smooth Muscle (metabolism)
• Pulmonary Arterial Hypertension (genetics)
• Pulmonary Artery (pathology)
• Rats
• Receptor, Endothelin A (metabolism)
• Zinc Finger Protein GLI1 (metabolism)