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Elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model
Hyun-Wook Lee1, Sung-Hyun Park1
1Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
Abstract:
Multiple causes are associated with the complex mechanism of pathogenesis of pulmonary arterial hypertension (PAH), but the molecular pathway in the pathogenesis of PAH is still insufficiently understood. In this study, we investigated epigenetic changes that cause PAH induced by exposure to combined Th2 antigen (Ovalbumin, OVA) and urban particulate matter (PM) in mice. To address that, we focused on the epigenetic mechanism, linked to microRNA (miR)-135a. We found that miR-135a levels were significantly increased, and levels of bone morphogenetic protein receptor type II (BMPR2) which is the target of miR-135a, were significantly decreased in this experimental PAH mouse model. Therefore to evaluate the role of miR-135a, we injected AntagomiR-135a into this mouse model. AntagomiR-135a injected mice showed decreased right ventricular systolic pressures (RVSPs), right ventricular hypertrophy (RVH), and the percentage of severely thickened pulmonary arteries compared to control scrambled miRNA injected mice. Both mRNA and protein expression of BMPR2 were recovered in the AntagomiR-135a injected mice compared to control mice. Our study understands if miR-135a could serve as a biomarker helping to manage PAH. The blocking of miR-135a could lead to new therapeutic modalities to alleviate exacerbation of PAH caused by exposure to Th2 antigen and urban air pollution.
Insights
This study reveals microRNA-135a (miR-135a) upregulation in a mouse model of pulmonary arterial hypertension (PAH). Blocking miR-135a improved PAH symptoms and restored BMPR2 levels, suggesting a therapeutic target.
Area of Science:
- Pulmonary Hypertension Research
- Epigenetics and Molecular Biology
- Environmental Health Science
Background:
- Pulmonary arterial hypertension (PAH) pathogenesis involves complex molecular pathways, with epigenetic mechanisms like microRNA dysregulation being insufficiently understood.
- Environmental factors, including Th2 antigen and urban particulate matter (PM), can contribute to PAH development.
Purpose of the Study:
- To investigate the role of microRNA-135a (miR-135a) in PAH induced by combined Th2 antigen and PM exposure in a mouse model.
- To explore miR-135a as a potential therapeutic target and biomarker for managing PAH.
Main Methods:
- Established a mouse model of PAH using Ovalbumin (OVA) and particulate matter (PM) exposure.
- Quantified miR-135a and bone morphogenetic protein receptor type II (BMPR2) levels.
- Administered AntagomiR-135a to inhibit miR-135a function and assessed PAH indicators and BMPR2 expression.
Main Results:
- miR-135a levels were significantly increased, while BMPR2 levels were decreased in the experimental PAH mouse model.
- Inhibition of miR-135a using AntagomiR-135a led to reduced right ventricular systolic pressures (RVSPs), right ventricular hypertrophy (RVH), and pulmonary artery thickening.
- BMPR2 mRNA and protein expression were restored in AntagomiR-135a treated mice.
Conclusions:
- miR-135a plays a crucial role in the pathogenesis of PAH induced by environmental exposures.
- Blocking miR-135a demonstrates therapeutic potential for alleviating PAH exacerbation.
- miR-135a may serve as a valuable biomarker for PAH management.