Abstract
There is growing evidence that microRNAs are implicated in pulmonary arterial hypertension (PAH), but underlying mechanisms remain elusive. Here, we identified that miR-223 was significantly downregulated in chronically hypoxic mouse and rat lungs, as well as in pulmonary artery and pulmonary artery smooth muscle cells (PASMC) exposed to hypoxia. Knockdown of miR-223 increased PASMC proliferation. In contrast, miR-223 overexpression abrogated cell proliferation, migration and stress fiber formation. Administering miR-223 agomir in vivo antagonized hypoxia-induced increase in pulmonary artery pressure and distal arteriole muscularization. RhoB, which was increased by hypoxia, was identified as one of the targets of miR-223. Overexpressed miR-223 suppressed RhoB and inhibited the consequent phosphorylation of myosin phosphatase target subunit (MYPT1) and the expression of myosin light chain of myosin II (MLC2), which was identified as another target of miR-223. Furthermore, serum miR-223 levels were decreased in female patients with PAH associated with congenital heart disease. Our study provides the first evidence that miR-223 can regulate PASMC proliferation, migration, and actomyosin reorganization through its novel targets, RhoB and MLC2, resulting in vascular remodeling and the development of PAH. It also highlights miR-223 as a potential circulating biomarker and a small molecule drug for diagnosis and treatment of PAH.
Highlights
Signaling pathways, such as the Rho-kinase pathway, are implicated as important factors in the pathogenesis of PAH1
This study reveals that miR-223 is rapidly downregulated in response to hypoxia in pulmonary artery smooth muscle cells (PASMC) and is critical to chronic hypoxia-associated pulmonary vascular pathology, such as smooth muscle cell proliferation, migration and actomyosin reorganization, which results in vascular remodeling and distal arteriole muscularization
We discovered a decrease in expression of miR-223 in hypoxia-induced pulmonary arterial hypertension (PAH) mouse lungs, pulmonary artery and isolated PASMC
Summary
Signaling pathways, such as the Rho-kinase pathway, are implicated as important factors in the pathogenesis of PAH1. Decrease in RhoB markedly inhibits hypoxia-induced endothelial permeability and growth responses in pulmonary vascular cells. Genetic deletion of RhoB attenuates development of chronic hypoxia-induced vascular remodeling and pulmonary hypertension in mice[5]. Decreased expression of miR-124 affects the proliferation, migration and inflammatory phenotype of both PASMC and pulmonary vascular fibroblasts[14,15]. Recent studies have indicated that miR-223 is an anti-angiogenic miRNA that prevents endothelial cell proliferation, migration and sprouting by targeting β 1 integrin[27]. We elucidated the role of miR-223 in pulmonary vascular responses to hypoxia in vitro and in vivo, and identified a RhoB/ myosin light chain-2 (MCL2)-dependent role of miR-223 in PASMC and its clinical importance as a potential biomarker for the diagnosis of pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH)
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