Elucidating the protective role of macrophage κ-opioid receptor (κ-OR)
Macrophage k-OR inhibits hypoxic pulmonary hypertension & right heart dysfunction via SCD1.
image: (A) Flow chart of the animal experiments. After 5 days of tamoxifen administration, κ-ORfl/fl and κ-ORΔMac mice were exposed to indoor air (normoxia) or 10% oxygen (hypoxia) plus weekly subcutaneous injection of SU5416 (10 mg/kg) for 4 weeks. (B, C) Mouse peritoneal macrophages were isolated 4 weeks after HPH, and κ-OR protein expression was analyzed by western blotting (n = 3 animals). (D–F) Echocardiography revealed changes in right ventricular wall thickness (RVWT) and tricuspid ring systolic displacement (TAPSE) values (n = 10 animals/group). (G, H) Changes in right ventricular systolic pressure were determined using a micro-pressure sensor (n = 9 animals/group). (I, J) Changes in the right heart hypertrophy index (n = 3 slices). *P <0.05 and **P <0.01. κ-ORfl/fl, mice with wild-type κ-OR in myeloid cells. κ-ORΔMac, mice with myeloid-specific deletion of κ-OR.
Credit: Qiaojuan Wang, Jiayuan Liu, Renqi Li, Sihan Kong, Yinjie Wang, Guoyang Huang, Shumiao Zhang, Na Feng, Xiaoming Gu, Yali Liu, Ming Jia, Feng Fu, Jun Li, Juan Li, Jianming Pei
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-ORΔMac) and their corresponding κ-ORfl/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-ORfl/fl + HPH group but was decreased in those of the κ-ORΔMac + 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
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