Inhibiting HIF ‐1α‐Induced miR ‐663b Improves Pulmonary Arterial Hypertension by Reducing Dysfunctions of PASMCs

ABSTRACT

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by vascular remodelling. Inflammatory responses and oxidative stress have been shown to contribute to its progression. This study investigated the effects of a novel HIF‐1α‐miR‐663b axis on pulmonary arterial smooth muscle inflammation, oxidative stress and apoptosis in a monocrotaline (MCT)‐induced PAH rat model. A PAH rat model was constructed via MCT injection; moreover, miR‐663b inhibitors were administered to inhibit miR‐663b. PASMCs were cultured under hypoxic conditions to establish an in vitro PAH model. The data revealed that miR‐663b was highly expressed in PAH rats and hypoxia‐induced PASMC models. Overexpression of miR‐663b exacerbated hypoxia‐induced proliferation, apoptosis, migration and inflammation in PASMCs. Conversely, miR‐663b inhibition reversed hypoxia‐induced dysfunction in PASMCs. ZBP1 downregulation dampened miR‐663b upregulation‐mediated dysfunctions in PASMCs. In vivo experiments revealed that miR‐663b inhibitors mitigated pulmonary arterial remodelling, inflammation and PANoptosis in MCT‐induced PAH rats. HIF‐1α expression was upregulated in hypoxia‐induced PASMCs. ChIP–qPCR and dual‐luciferase reporter gene assays confirmed that HIF‐1α transcriptionally regulated and promoted miR‐663b expression. Upregulation of miR‐663b inhibited AMPK/Sirt1 signalling pathway activation and promoted ZBP1‐mediated PANoptosis. However, miR‐663b inhibitors reversed hypoxia‐induced PANoptosis in PASMCs. The protective effects of miR‐663b inhibitors on PASMCs and their inhibitory effects on PANoptosis were significantly weakened by treatment with an AMPK inhibitor or a Sirt1 inhibitor. Collectively, these findings suggest that inhibiting HIF‐1α‐mediated miR‐663b expression improves PAH by reducing PASMC dysfunction through the attenuation of inflammatory responses, oxidative stress and apoptosis in PASMCs and the activation of the AMPK/Sirt1 pathway.