PUBLICATION
Macrophage P2Y12 regulates iron transport and its inhibition protects against atherosclerosis
- Authors
- Hu, Y.X., You, H.M., Bai, M.R., Yue, W.H., Li, F.F., Hu, B.W., Chen, Y.S., Shen, X.Y., Wu, Y., Wang, J.M., He, Z.Q., Tao, X., Jing, Q., Liang, C.
- ID
- ZDB-PUB-241215-4
- Date
- 2024
- Source
- Journal of advanced research : (Journal)
- Registered Authors
- Hu, Yang-Xi, Jing, Qing, Li, Fangfang
- Keywords
- Antiplatelet therapy, Atherosclerosis, Ferroptosis, Iron overload, Macrophage, P2Y12
- MeSH Terms
-
- Humans
- Disease Models, Animal
- Receptors, Purinergic P2Y12*/genetics
- Receptors, Purinergic P2Y12*/metabolism
- Macrophages*/metabolism
- Iron Overload/metabolism
- Iron*/blood
- Iron*/metabolism
- Zebrafish
- Female
- Macrophages, Peritoneal*/metabolism
- Case-Control Studies
- Purinergic P2Y Receptor Antagonists/pharmacology
- Mice
- Biological Transport
- Male
- Atherosclerosis*/metabolism
- Atherosclerosis*/pathology
- Atherosclerosis*/prevention & control
- Animals
- PubMed
- 39674499 Full text @ J Adv Res
Citation
Hu, Y.X., You, H.M., Bai, M.R., Yue, W.H., Li, F.F., Hu, B.W., Chen, Y.S., Shen, X.Y., Wu, Y., Wang, J.M., He, Z.Q., Tao, X., Jing, Q., Liang, C. (2024) Macrophage P2Y12 regulates iron transport and its inhibition protects against atherosclerosis. Journal of advanced research. :.
Abstract
Introduction Iron retention is commonly observed in atherosclerotic plaques and is believed to be detrimental to atherosclerosis. Platelet P2Y12 is a target of antiplatelet therapy in preventing thrombotic complications of atherosclerosis. The protective effect of P2Y12 on hematopoiesis reported by our previous work implies the involvement of P2Y12 in iron metabolism.
Objectives This study further investigated the role of P2Y12 in the iron metabolism of macrophages, the key player in systemic iron homeostasis and atherosclerosis.
Methods The association between serum iron and the use of P2Y12 inhibitors was evaluated by a case-control study in human. Secondary iron overload and atherosclerosis animal models were established in P2Y12-deficient zebrafish to explore the role of P2Y12 in macrophage iron metabolism in vivo. Both iron-overloaded murine primary peritoneal macrophages (PMs) and ox-LDL-treated PMs with P2Y12 knockdown were used for in vitro studies. RNA sequencing and pharmacological approaches were performed to investigate the downstream mechanisms.
Results Increased serum iron level was positively associated with P2Y12 inhibitor usage [odds ratio (OR) = 10.333 (1.281-83.370)]. Elevated serum iron level and transferrin saturation, reduced hepatic and splenic iron content, and decreased iron staining in macrophages were observed in secondary iron overload P2Y12-deficient zebrafish. Deficiency of P2Y12 in ApoEb-/- zebrafish fed a high-fat diet reduced atherosclerosis progression and intraplaque iron retention. Furthermore, reduced ferritin, restored cell viability and expression of ferroptosis marker proteins, and decreased ROS formation and inflammatory cytokines were observed in both iron-overloaded and ox-LDL-treated PMs with P2Y12 knockdown in vitro, while reversed phenotypes were observed after agonist-induced P2Y12 activation. Mechanistically, P2Y12 inhibition in iron-overloaded or ox-LDL-treated PMs suppressed NF-κB p65 phosphorylation and hepcidin expression, both of which were reversed by P2Y12 activation.
Conclusion P2Y12 inhibition decreased hepcidin autocrine through repressing NF-κB p65 phosphorylation in macrophages, preventing intracellular iron retention and atherosclerosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping