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Negative feedback regulation between microRNA let-7g and LOX-1 mediated hypoxia-induced PASMCs proliferation
Wei-Fang Zhang1, Tian-Tian Zhu2, You-Wen Xiong3
1Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Biochemical and Biophysical Research Communications
|January 22, 2017
Summary
MicroRNA let-7g and LOX-1 exhibit negative feedback in pulmonary hypertension. This interaction regulates pulmonary artery smooth muscle cell proliferation under hypoxic conditions, offering potential therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pulmonary Hypertension Research
Background:
- Pulmonary hypertension (PH) is characterized by excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs).
- Previous research indicated that let-7g inhibits hypoxia-induced PASMC proliferation by targeting the c-myc-Bmi-1-p16 pathway.
- The upstream regulators of let-7g, particularly its interaction with LOX-1, remained incompletely understood in the context of PH.
Purpose of the Study:
- To investigate the potential negative feedback loop between microRNA let-7g and LOX-1.
- To elucidate the role of this feedback mechanism in hypoxia-induced PASMC proliferation.
- To explore the involvement of specific molecular players in this regulatory pathway.
Main Methods:
- Hypoxia-induced pulmonary hypertension model in Sprague-Dawley rats.
- Assessment of pulmonary artery remodeling using HE staining.
- Evaluation of let-7g and LOX-1 expression via in situ hybridization and immunohistochemistry.
- Analysis of PASMC proliferation using MTS, EDU assays, and flow cytometry.
- Gene and protein expression analysis of let-7g, LOX-1, calpains, and OCT-1 using qRT-PCR and Western blotting.
Main Results:
- Hypoxia-induced PH in rats showed decreased let-7g expression and pulmonary vascular remodeling.
- Let-7g mimic administration suppressed hypoxia-induced PASMC proliferation and increased LOX-1 expression.
- Blocking LOX-1 reversed the hypoxia-induced downregulation of let-7g.
- Calpains, protein kinase C, and OCT-1 were identified as key mediators in the let-7g/LOX-1 negative feedback.
Conclusions:
- A negative feedback mechanism exists between let-7g and LOX-1 in PASMCs.
- This let-7g/LOX-1 feedback loop plays a critical role in mediating hypoxia-induced PASMC proliferation.
- Targeting this pathway may offer novel therapeutic strategies for pulmonary hypertension.
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