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Disturbance of suprachiasmatic nucleus function improves cardiac repair after myocardial infarction by IGF2-mediated macrophage transition

Acta Pharmacologica Sinica volume 44, pages 1612–1624 (2023)Cite this article

Abstract

Suprachiasmatic nucleus (SCN) in mammals functions as the master circadian pacemaker that coordinates temporal organization of physiological processes with the environmental light/dark cycles. But the causative links between SCN and cardiovascular diseases, specifically the reparative responses after myocardial infarction (MI), remain largely unknown. In this study we disrupted mouse SCN function to investigate the role of SCN in cardiac dysfunction post-MI. Bilateral ablation of the SCN (SCNx) was generated in mice by electrical lesion; myocardial infarction was induced via ligation of the mid-left anterior descending artery (LAD); cardiac function was assessed using echocardiography. We showed that SCN ablation significantly alleviated MI-induced cardiac dysfunction and cardiac fibrosis, and promoted angiogenesis. RNA sequencing revealed differentially expressed genes in the heart of SCNx mice from D0 to D3 post-MI, which were functionally associated with the inflammatory response and cytokine-cytokine receptor interaction. Notably, the expression levels of insulin-like growth factor 2 (Igf2) in the heart and serum IGF2 concentration were significantly elevated in SCNx mice on D3 post-MI. Stimulation of murine peritoneal macrophages in vitro with serum isolated from SCNx mice on D3 post-MI accelerated the transition of anti-inflammatory macrophages, while antibody-mediated neutralization of IGF2 receptor blocked the macrophage transition toward the anti-inflammatory phenotype in vitro as well as the corresponding cardioprotective effects observed in SCNx mice post-MI. In addition, disruption of mouse SCN function by exposure to a desynchronizing condition (constant light) caused similar protective effects accompanied by elevated IGF2 expression on D3 post-MI. Finally, mice deficient in the circadian core clock genes (Ckm-cre; Bmal1f/f mice or Per1/2 double knockout) did not lead to increased serum IGF2 concentration and showed no protective roles in post-MI, suggesting that the cardioprotective effect observed in this study was mediated particularly by the SCN itself, but not by self-sustained molecular clock. Together, we demonstrate that inhibition of SCN function promotes Igf2 expression, which leads to macrophage transition and improves cardiac repair post-MI.

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Fig. 1: SCN ablation in mice attenuated MI-induced cardiac injury during ZT5 and ZT13.
Fig. 2: SCN ablation in mice ameliorated MI-induced cardiac fibrosis and promoted angiogenesis.
Fig. 3: SCN ablation led to the changes on cardiac transcriptome on day 3 post-MI.
Fig. 4: SCN ablation modulated anti-inflammatory macrophage switch in the mouse heart post-MI.
Fig. 5: IGF2 promoted macrophage reprogramming in SCNx mice.
Fig. 6: IGF2R antibody treatment abolished the protective effect of SCN ablation against MI-induced cardiac injury.
Fig. 7: IGF2R antibody treatment disturbed anti-fibrotic and anti-inflammatory effect of SCN ablation.
Fig. 8: Disturbance of suprachiasmatic nucleus function preserves cardiac function by IGF2-mediated macrophage transition.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2022YFA1104300, 2018YFA0801100, 2021YFA1101902), the National Natural Science Foundation of China (82241202, 31630091, 82170364, 81970223), the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD) and National Center for International Research (2017B01012), the Natural Science Foundation of Jiangsu Province (BK20201409), Jiangsu Province’s Key Discipline/Laboratory of Medicine (XK201118) and Introduction Project of Clinical Medicine Expert Team for Suzhou (SZYJTD201704), Lingang Laboratory & National Key Laboratory of Human Factors Engineering Joint Grant (LG-TKN-202203-01).

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  1. These authors contributed equally: Kai-li Hao, Qiao-cheng Zhai, Yue Gu.

Authors and Affiliations

  1. Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China

    Kai-li Hao, Yue-qiu Chen, Ya-ning Wang, Shi-ping Yan, Wei Lei, Zhen-ya Shen & Shi-jun Hu

  2. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China

    Qiao-cheng Zhai, Yue Gu & Ying Xu

  3. The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College, Soochow University, Suzhou, 215123, China

    Rui Liu & Yu-fang Shi

  4. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China

    Ying Wang

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Contributions

KLH performed the heart-related experiment. QCZ performed bilateral SCN lesions in mice and conducted other clock mutant mice models. YG worked on RNA-Seq data analysis. YQC and RL performed flow cytometric analysis. YNW and SPY performed immunofluorescence staining. YFS, YW, WL, ZYS, YX, and SJH conceived and designed the experiments. KLH, WL, YX, and SJH wrote the manuscript. All authors read, edited, and approved the manuscript.

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Correspondence to Wei Lei, Zhen-ya Shen, Ying Xu or Shi-jun Hu.

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Hao, Kl., Zhai, Qc., Gu, Y. et al. Disturbance of suprachiasmatic nucleus function improves cardiac repair after myocardial infarction by IGF2-mediated macrophage transition. Acta Pharmacol Sin 44, 1612–1624 (2023). https://doi.org/10.1038/s41401-023-01059-w

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