Hypoxic pulmonary hypertension (HPH), or hypoxia-induced PH, is a chronic, progressive cardiovascular disease characterized by sustained vasoconstriction and vascular remodelling, but the mechanisms underlying pulmonary vascular remodelling are poorly understood.

A recent study published in the Genes & Diseases journal by researchers at the Air Force Medical University investigated the role of macrophage κ-opioid receptor (κ-OR) on pulmonary inflammation in HPH and elucidated its underlying regulatory molecular mechanism. The authors had previously identified that κ-OR activation by the exogenous agonist U50,488H effectively mitigates HPH; however, its role in lung inflammation remains to be investigated.

In this study, the authors first generated mice with myeloid-specific deletion of κ-OR (κ-OR^ΔMac) and their corresponding κ-OR^fl/fl littermate controls. These mice were then subjected to a hypobaric hypoxia simulation chamber, along with a subcutaneous injection of SU5416, for four weeks to establish HPH models. Subsequent experiments revealed that κ-OR expression decreased during HPH, while its knockdown exacerbated HPH. Furthermore, knockdown of macrophage κ-OR increased hypoxia-induced M1 macrophage infiltration, promoted perivascular inflammation, and pulmonary artery remodeling, ultimately leading to cardiac dysfunction.

Mouse peritoneal macrophages treated with LPS had increased CD86 mRNA expression but decreased CD206 mRNA and κ-OR protein expression. Knockdown of macrophage κ-OR increased the expression and release of inflammatory cytokines upon LPS stimulation. Additionally, LPS-induced macrophages treated with U50,488H showed a decreased inflammatory response. Together, these observations establish that activation of κ-OR elicits an anti-inflammatory effect in macrophages.

In co-culture experiments with macrophages and pulmonary artery smooth muscle cells (PASMCs), the κ-OR agonist U50,488H inhibited both the macrophage inflammatory response and PASMC proliferation, suggesting that κ-OR activation in macrophages exerts anti-proliferative effects on PASMCs through a paracrine mechanism.

RNA sequencing and KEGG analysis identified differentially expressed genes enriched in inflammatory response and lipid metabolism-related pathways. Real-time PCR analysis of the genes involved in lipid metabolism identified that SCD1, a pivotal regulator of lipid homeostasis involved in metabolic syndrome development and inflammation, was significantly increased in the peritoneal macrophages of the κ-OR^fl/fl + HPH group but was decreased in those of the κ-OR^ΔMac + HPH group. SCD1 overexpression suppressed the inflammatory response in LPS-treated macrophages, suggesting that SCD1 may inhibit HPH by attenuating the inflammatory response.

In conclusion, this study demonstrated that macrophage κ-OR inhibits HPH and cardiac dysfunction via a SCD1-dependent anti-inflammatory response, thus providing new insights into the cellular and molecular mechanisms underlying the protective role of macrophage κ-OR in HPH.

Reference

Title of the original paper: Macrophage κ-opioid receptor inhibits hypoxic pulmonary hypertension progression and right heart dysfunction via an SCD1-dependent anti-inflammatory response

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch

DOI: https://doi.org/10.1016/j.gendis.2025.101604

Funding Information:

• Program for National Science Funds of China (No. 82070051)
• Natural Science Basic Research Key Project of Shaanxi Province, China (No. 2022JZ-55)
• National Defense Foundation Strengthening Project of the Science and Technology Commission (China) (No. JSLY-27-B27004)
• Air Force Military Medical University Cross-Integration Project (China) (No. 2023JC017)
• Military Medical Advancement Program of Air Force Military Medical University (China) (No. 2021JSTS11)
• Key Research and Development Projects of Shaanxi Province, China (No. 2023-YBSF-373).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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