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Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function

Authors :
Joana Santos-Gomes
Pedro Mendes-Ferreira
Rui Adão
Carolina Maia-Rocha
Beatriz Rego
Manu Poels
Anaïs Saint-Martin Willer
Bastien Masson
Steeve Provencher
Sébastien Bonnet
David Montani
Frédéric Perros
Fabrice Antigny
Adelino F. Leite-Moreira
Carmen Brás-Silva
Source :
International Journal of Molecular Sciences, Vol 25, Iss 15, p 8054 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
25
Issue :
15
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.73b910647364264af294cd9257363c7
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms25158054