Exosomal miR-21 mitigates pulmonary hypertension-induced right-heart remodeling by preserves mitochondrial homeostasis

RATIONALE: Right ventricular (RV) dysfunction is the principal determinant of prognosis in pulmonary arterial hypertension (PAH), yet the molecular mediators linking pulmonary vascular stress to RV remodeling remain incompletely understood. Exosomal microRNAs (miRNAs) have emerged as paracrine messengers capable of mediating inter-organ communication. This study investigated the role of exosomal miR-21 in pulmonary vascular–RV cross-talk in PAH. METHODS: Exosomes were isolated from right-heart catheterization samples of PAH patients and analyzed by next-generation sequencing to identify enriched miRNAs. Functional studies were performed using hypoxia-stimulated human pulmonary microvascular endothelial cells (HMECs)-derived exosomes applied to cardiomyocytes. In vivo validation included Sugen/hypoxia (SuHx)-induced PAH in wild-type and miR-21 knockout (miR-21−/−) mice, complemented by parabiosis experiments to test systemic exosomal transfer. RESULTS: Exosomal miR-21 was markedly enriched in the pulmonary circulation of PAH patients. Hypoxia upregulated miR-21 in HMECs-derived exosomes, which were internalized by cardiomyocytes, reducing apoptosis and protecting against mitochondrial dysfunction via SPRY2/p-ERK and PTEN/AKT signaling. In SuHx models, miR-21−/− mice developed more severe RV remodeling, fibrosis, and mitochondrial gene suppression. Parabiosis demonstrated that wild-type partners conferred RV protection to miR-21−/− mice with an increasing expression of miR-21 and attenuated pulmonary arterial pressure and remodeling, whereas miR-21−/− pairs exhibited exacerbated RV impairment. CONCLUSIONS: Endothelial-derived exosomal miR-21 is upregulated by hypoxia and associated with cardioprotective effects by limiting apoptosis and mitochondrial dysfunction in adjacent cardiomyocytes. These findings identify exosomal miR-21 as a key mediator associated with RV adaptation and support its potential as a biomarker and therapeutic target in PAH.