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Published on: September 19, 2016
Resveratrol prevented experimental pulmonary vascular remodeling via miR-638 regulating NR4A3/cyclin D1 pathway
Ying-Ying Liu1, Wei-Yun Zhang1, Chang-Guo Wang1
1Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Objective:
Resveratrol has shown benefit for pulmonary hypertension improvement. Our previous reports showed NR4A3/cyclin D1 pathway promoted pulmonary arterial smooth muscle cells (PASMCs) proliferation. This study tried to explore the mechanism underlying this process, focusing on the role of resveratrol in regulation of miRNA and NR4A3.
Methods:
Rats were injected with monocrotaline (MCT) to establish pulmonary hypertension (PH) models. Resveratrol was used to prevent pulmonary vascular remodeling. Primary rat PASMCs were cultured in vitro and stimulated by platelet-derived growth factor (PDGF) with or without resveratrol. Cells proliferation and expression of miR-638 as well as NR4A3 were evaluated.
Results:
MCT resulted in significant pulmonary vascular remodeling and down-regulation of miR-638, which could be suppressed by resveratrol. Moreover, PDGF-induced PASMC proliferation and miR-638 down-regulation were both significantly prevented by resveratrol treatment in vitro. MiR-638 mimics markedly inhibited PASMC proliferation and percentage of PCNA-positive cells in vitro. But anti-miR-638 could markedly promote cells proliferation and percentage of PCNA-positive cells. The luciferase reporter assay showed that NR4A3 was a direct target of miR-638. The loss-of-function and gain-of-function experiments indicated that NR4A3 promoted proliferation via cyclin D1 pathway.
Conclusion:
Our data indicated that resveratrol prevented MCT-induced pulmonary vascular remodeling via miR-638 regulating NR4A3/cyclin D1 pathway.
Insights
Resveratrol prevents pulmonary hypertension by regulating miR-638, which targets NR4A3. This mechanism inhibits proliferation of pulmonary arterial smooth muscle cells (PASMCs) and prevents vascular remodeling.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Cell Biology
Background:
- Pulmonary hypertension (PH) involves pulmonary arterial smooth muscle cell (PASMC) proliferation.
- The NR4A3/cyclin D1 pathway is implicated in PASMC proliferation.
- Resveratrol has shown potential benefits in improving PH.
Purpose of the Study:
- To investigate the mechanism by which resveratrol regulates miRNA and NR4A3 in PH.
- To explore resveratrol's role in the NR4A3/cyclin D1 pathway in PASMCs.
Main Methods:
- Established PH rat models using monocrotaline (MCT).
- Cultured primary rat PASMCs and treated with platelet-derived growth factor (PDGF) ± resveratrol.
- Assessed cell proliferation, miR-638 and NR4A3 expression, and performed luciferase reporter assays.
Main Results:
- MCT induced pulmonary vascular remodeling and decreased miR-638, which resveratrol counteracted.
- Resveratrol inhibited PDGF-induced PASMC proliferation and miR-638 downregulation in vitro.
- miR-638 directly targets NR4A3, and NR4A3 promotes proliferation via the cyclin D1 pathway.
Conclusions:
- Resveratrol prevents MCT-induced pulmonary vascular remodeling.
- The protective effect of resveratrol involves the miR-638 regulation of the NR4A3/cyclin D1 pathway in PASMCs.
