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Macrophage ferroptosis potentiates GCN2 deficiency induced pulmonary venous arterialization
Jingyuan Zhang1,2, Pei Mao1,2, Tengfei Zhou1,2
1Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Pulmonary veno-occlusive disease (PVOD) is a fatal disease characterized by the remodelling of pulmonary veins and haemosiderin accumulation in macrophages. Although (General Control Nonderepressible 2) GCN2 deficiency has been reported in PVOD patients, the underlying mechanism by which GCN2 deficiency affects the pulmonary venous cells and the surrounding cells, remains unclear. Here, we perform immunohistochemistry and scRNA-sequencing analyses to show that macrophages are the major population affected by GCN2 deficiency and ferroptosis pathway-related genes are upregulated in lung macrophages of PVOD patients. Treatment with the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) reverses the changes in haemodynamic indices observed in Eif2ak4K1488X/K1488X hypoxia mice and PVOD model rats. Furthermore, GCN2 deficiency increases HMOX1 and iron levels to facilitate ferroptosis in macrophages, and enhances arterial marker expression in venous endothelial cells (VECs). Specifically, spatial transcriptome analysis shows increased expression of NRP1, KDR and EFNB2 through ETS1 in VECs from PVOD patients. Our findings suggest the potential of targeting macrophage ferroptosis as a therapeutic strategy for treating related vascular diseases, and of using NRP1/KDR/EFNB2 expression as a specific marker set for venous arterialization.
Insights
General Control Nonderepressible 2 (GCN2) deficiency in pulmonary veno-occlusive disease (PVOD) affects macrophages, promoting ferroptosis. Targeting this pathway offers a potential therapeutic strategy for PVOD.
Area of Science:
- Pulmonary vascular disease research
- Cellular mechanisms of disease
- Macrophage biology
Background:
- Pulmonary veno-occlusive disease (PVOD) is fatal, marked by pulmonary vein remodeling and macrophage haemosiderin.
- The role of General Control Nonderepressible 2 (GCN2) deficiency in PVOD pathogenesis is not fully understood.
- Investigating GCN2's impact on pulmonary venous and surrounding cells is crucial.
Purpose of the Study:
- To elucidate the mechanism of GCN2 deficiency in PVOD.
- To identify cellular targets and pathways involved in PVOD.
- To explore potential therapeutic strategies for PVOD.
Main Methods:
- Immunohistochemistry and single-cell RNA sequencing (scRNA-seq) on PVOD patient samples.
- Pharmacological inhibition of ferroptosis using ferrostatin-1 (Fer-1).
- Analysis of hemodynamic indices in mouse and rat PVOD models.
- Spatial transcriptome analysis to identify gene expression patterns in VECs.
Main Results:
- Macrophages are significantly affected by GCN2 deficiency in PVOD, with upregulated ferroptosis pathway genes.
- Ferrostatin-1 treatment reversed hemodynamic changes in PVOD models.
- GCN2 deficiency increases macrophage iron and HMOX1 levels, promoting ferroptosis.
- Venous endothelial cells (VECs) showed enhanced arterial marker expression (NRP1, KDR, EFNB2) via ETS1 in PVOD patients.
Conclusions:
- Targeting macrophage ferroptosis presents a potential therapeutic avenue for PVOD and related vascular diseases.
- NRP1, KDR, and EFNB2 expression serve as specific markers for venous arterialization in PVOD.
- GCN2 deficiency plays a key role in PVOD pathogenesis through macrophage ferroptosis and VEC alterations.
