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Updated: May 21, 2026
Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension
Published on: April 11, 2016
A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples
Paola Caruso1, Yvonne Dempsie, Hannah C Stevens
1Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Rationale:
Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling.
Objective:
We assessed the role of miR-145 in PAH.
Methods And Results:
We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice.
Conclusions:
miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.
Insights
Downregulating microRNA-145 (miR-145) protects against pulmonary arterial hypertension (PAH) development. This microRNA is upregulated in PAH patients and mouse models, suggesting miR-145 manipulation as a potential PAH treatment.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Genetics
Background:
- Pulmonary arterial hypertension (PAH) is a severe vascular disease characterized by pulmonary artery remodeling.
- MicroRNAs (miRNAs) are implicated in vascular remodeling processes relevant to PAH.
- Understanding the genetic underpinnings of PAH is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of microRNA-145 (miR-145) in the pathogenesis of pulmonary arterial hypertension (PAH).
- To determine if miR-145 dysregulation contributes to vascular remodeling in PAH.
- To explore the therapeutic potential of targeting miR-145 in PAH.
Main Methods:
- Quantitative PCR was used to assess miR-145 expression in mouse lungs under hypoxic conditions.
- miR-145 knockout mice and anti-miR treatments were employed to evaluate the effects of miR-145 deficiency on PAH development.
- Systolic right ventricular pressure, right ventricular hypertrophy, and pulmonary artery remodeling were measured.
- Lung tissues from human PAH patients and BMPR2-deficient mice were analyzed for miR-145 expression.
Main Results:
- miR-145 expression was increased in wild-type mice exposed to hypoxia.
- Deficiency or inhibition of miR-145 significantly protected against the development of PAH in mouse models.
- miR-145 was found to be upregulated in lung tissues of patients with idiopathic and heritable PAH.
- Elevated miR-145 levels were observed in primary pulmonary artery smooth muscle cells (PASMCs) from patients with BMPR2 mutations and in BMPR2-deficient mice.
Conclusions:
- miR-145 is dysregulated in both experimental models and human PAH.
- Downregulation of miR-145 confers protection against PAH development.
- Mutations in BMPR2 are associated with increased miR-145 expression, linking genetic factors to miRNA involvement in PAH.
- Targeting miR-145 presents a novel therapeutic strategy for pulmonary arterial hypertension.
