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Updated: Jun 4, 2026
Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension
Published on: April 11, 2016
Role for miR-204 in human pulmonary arterial hypertension
Audrey Courboulin1, Roxane Paulin, Nellie J Giguère
1Département de médecine, Faculté de médecine, Hôtel-Dieude Québec, Canada.
Abstract:
Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.
Insights
MicroRNA-204 (miR-204) is down-regulated in pulmonary arterial hypertension (PAH), driving cell overgrowth and survival. Restoring miR-204 levels in the lungs reduced PAH severity in animal models.
Area of Science:
- Molecular biology
- Cardiovascular research
- Cell biology
Background:
- Pulmonary arterial hypertension (PAH) involves abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis.
- MicroRNAs are increasingly recognized for their roles in regulating cell growth and programmed cell death.
Purpose of the Study:
- To investigate the role of microRNAs in the etiology of PAH.
- To identify specific microRNAs and their regulatory pathways involved in PAH pathogenesis.
Main Methods:
- Quantitative real-time PCR to measure miR-204 expression in human and rodent PASMCs.
- Western blotting and luciferase assays to identify miR-204 targets and signaling pathways.
- In vivo studies involving delivery of synthetic miR-204 to animal models of PAH.
Main Results:
- miR-204 expression is significantly reduced in PASMCs from patients and animals with PAH.
- Down-regulation of miR-204 promotes PASMC proliferation and inhibits apoptosis by targeting SHP2, leading to Src kinase and NFAT activation.
- STAT3 activation suppresses miR-204, while miR-204 targets SHP2, which activates Src and NFAT.
- Administration of synthetic miR-204 to the lungs ameliorated PAH severity in vivo.
Conclusions:
- A novel regulatory pathway involving miR-204, STAT3, SHP2, Src, and NFAT is critical in PAH.
- Restoring miR-204 expression represents a potential therapeutic strategy for pulmonary arterial hypertension.
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