Metabolism: clinical and experimental · 2026
ATF6 contributes to cardiac macrophage polarization and metabolic reprogramming following myocardial ischemia/reperfusion injury.
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Wu Zimin, Mo Sisi, Huang Zuyuan, Zhang Chuanliang, Zheng Baoshi
Аннотация
OBJECTIVE: To investigate when and how activating transcription factor 6 (ATF6) contributes to macrophages (Mφ) polarization and tissue repair after myocardial ischemia/reperfusion (I/R) injury.
METHODS: The WT and ATF6 knockout (ATF6-/-) mice were subjected to myocardial I/R injury. Endoplasmic reticulum stress (ERS) markers expression levels were detected by western blotting. Echocardiography, Masson staining, Sirius red staining, Evans Blue/TTC staining and immunofluorescence techniques were used to evaluate myocardial injury context and cardiac function. Flow cytometry analyzed the phenotypes and functions of cardiac Mφ (cMφ). Single-cell sequencing technology, Seahorse oxygen consumption rate/extracellular acidification rate assays and reactive oxygen species (ROS) measurements were used to analyze how ATF6 deficiency affects the profiles of cMφ.
RESULTS: Myocardial I/R injury resulted in an increase expression of ERS markers with ATF6 hydrolyzed and entered the nucleus. The role of heart in recruiting peripheral monocyte-derived CCR2+ cMφ and driving their phenotypic transformation from pro-inflammatory (CCR2+Ly6C+CD206- cMφ) to reparative (CCR2+Ly6C-CD206+ cMφ) is impaired in ATF6-/- mice. Moreover, the myocardial injured exacerbated, cardiac function recovery delayed and adverse early remodeling occurred, which could not be salvaged by Mφ adoptive adoption. Single-cell sequencing revealed that differentially expressed genes in CCR2+Ly6C-CD206+ cMφ of WT and ATF6-/- mice and were enriched in ROS and oxidative phosphorylation signaling pathways. Functional metabolic assays in CCR2+Ly6C-CD206+ bone marrow-derived macrophage demonstrated that ATF6 deficiency was associated with impaired mitochondrial respiration (reduced basal respiration, maximal respiratory capacity, ATP production and spare respiratory capacity) with a compensatory glycolytic upregulation, and increased ROS production, which was abrogated by the mitochondria-targeted scavenger.
CONCLUSION: ATF6 deficiency is associated with altered phenotype and function of monocyte-derived CCR2+ cMφ during myocardial I/R injury. This association between ATF6 and improved outcomes might be linked to phenotypic polarization and metabolic fitness of CCR2+Ly6C-CD206+ cMφ.
METHODS: The WT and ATF6 knockout (ATF6-/-) mice were subjected to myocardial I/R injury. Endoplasmic reticulum stress (ERS) markers expression levels were detected by western blotting. Echocardiography, Masson staining, Sirius red staining, Evans Blue/TTC staining and immunofluorescence techniques were used to evaluate myocardial injury context and cardiac function. Flow cytometry analyzed the phenotypes and functions of cardiac Mφ (cMφ). Single-cell sequencing technology, Seahorse oxygen consumption rate/extracellular acidification rate assays and reactive oxygen species (ROS) measurements were used to analyze how ATF6 deficiency affects the profiles of cMφ.
RESULTS: Myocardial I/R injury resulted in an increase expression of ERS markers with ATF6 hydrolyzed and entered the nucleus. The role of heart in recruiting peripheral monocyte-derived CCR2+ cMφ and driving their phenotypic transformation from pro-inflammatory (CCR2+Ly6C+CD206- cMφ) to reparative (CCR2+Ly6C-CD206+ cMφ) is impaired in ATF6-/- mice. Moreover, the myocardial injured exacerbated, cardiac function recovery delayed and adverse early remodeling occurred, which could not be salvaged by Mφ adoptive adoption. Single-cell sequencing revealed that differentially expressed genes in CCR2+Ly6C-CD206+ cMφ of WT and ATF6-/- mice and were enriched in ROS and oxidative phosphorylation signaling pathways. Functional metabolic assays in CCR2+Ly6C-CD206+ bone marrow-derived macrophage demonstrated that ATF6 deficiency was associated with impaired mitochondrial respiration (reduced basal respiration, maximal respiratory capacity, ATP production and spare respiratory capacity) with a compensatory glycolytic upregulation, and increased ROS production, which was abrogated by the mitochondria-targeted scavenger.
CONCLUSION: ATF6 deficiency is associated with altered phenotype and function of monocyte-derived CCR2+ cMφ during myocardial I/R injury. This association between ATF6 and improved outcomes might be linked to phenotypic polarization and metabolic fitness of CCR2+Ly6C-CD206+ cMφ.