Macrophage-specific κ-OR knockout exacerbates inflammation in hypoxic pulmonary hypertension

Hypoxic pulmonary hypertension (HPH), a prevalent subtype of pulmonary arterial hypertension, is characterized by pulmonary vasoconstriction (HPV) and vascular remodeling, accompanied by inflammatory responses. Recent in vivo studies have shown a critical role of the κ-opioid receptor (κ-OR) in modulating the aforementioned pathological processes. Specifically, macrophage-specific κ-OR-knockout models have shown inflammatory response exacerbation with pulmonary hypertension and vascular remodeling. Conversely, the novel κ-OR agonist Q-U50, 488H inhibits inflammatory pathways, thereby attenuating pulmonary vasoconstriction and vascular remodeling. The present study revealed that hypoxia promoted macrophage infiltration and pulmonary artery smooth muscle cell proliferation. Moreover, under these conditions, macrophages secreted interleukin (IL)-6, which triggered the signal transducer and activator of transcription 3 (STAT3)/miR-153-3p signaling cascade. Herein, we identified miR-153-3p downregulated κ-OR gene expression, which is a key contributor to HPV and remodeling, it was identified as a pivotal regulator of κ-OR mRNA levels. The pharmacological activation of κ-OR inhibited IL-6 release from macrophages and disrupted the IL-6/STAT3/miR-153-3p pathway. This dual action of κ-OR activation mitigated pulmonary artery contraction and remodeling, thereby offering a protective mechanism against HPH. The present findings have delineated a novel negative feedback loop driving HPH pathogenesis and suggested that targeting the κ-OR-IL-6-STAT3-miR-153-3p axis represented a promising therapeutic strategy against HPH.