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Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis

Acta Pharmacologica Sinica volume 45, pages 728–737 (2024)Cite this article

Abstract

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

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Fig. 1: CCL2 expression is increased in the mouse heart after MI.
Fig. 2: CCL2 ameliorates cardiac remodeling after MI.
Fig. 3: CCL2 promotes heart regeneration after MI.
Fig. 4: CCL2 promotes cardiomyocyte proliferation in vivo.
Fig. 5: CCL2 induces cardiomyocyte proliferation in vitro.
Fig. 6: Activation of STAT3 signaling in cardiomyocytes after recombinant CCL2 stimulation.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (81930008, 81900792), the Natural Science Foundation of Chongqing (2023NSCQ-MSX2101), the National Key R&D Program of China (2018YFC1312700), the Program of Innovative Research Team by the National Natural Science Foundation (81721001), and the Program for Changjiang Scholars and Innovative Research Team in University; IRT1216.

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  1. These authors contributed equally: Wei Wang, Xiao-kang Chen

Authors and Affiliations

  1. Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400042, China

    Wei Wang, Xiao-kang Chen, Lu Zhou, Feng Wang, Yan-ji He, Bing-jun Lu, Zhu-xin Li, Xue-wei Xia, Chun-yu Zeng & Liang-peng Li

  2. Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, 400042, China

    Wei Wang, Xiao-kang Chen, Lu Zhou, Feng Wang, Yan-ji He, Bing-jun Lu, Zhu-xin Li, Xue-wei Xia, Chun-yu Zeng & Liang-peng Li

  3. Department of Laboratory Animal Center, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400042, China

    Ze-gang Hu

  4. Department of Geriatrics, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Wei Eric Wang

  5. State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400042, China

    Chun-yu Zeng

  6. Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, 400714, China

    Chun-yu Zeng

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Contributions

WW, LPL, and CYZ conceived the study, designed the experiments and wrote the manuscript; WW performed immunofluorescence staining, enzyme-linked immunosorbent assays, real-time PCR, and endothelial tube formation assays; XKC generated the animal model and performed Masson staining analysis; LZ and FW performed echocardiography and evaluated heart function; YJH performed western blotting; BJL and ZXL performed data analysis; ZGH performed several experiments related to the animal model; XWX isolated and cultured primary cardiomyocytes; WEW, LPL and CYZ revised the manuscript. All authors approved the manuscript.

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Correspondence to Chun-yu Zeng or Liang-peng Li.

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Wang, W., Chen, Xk., Zhou, L. et al. Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis. Acta Pharmacol Sin 45, 728–737 (2024). https://doi.org/10.1038/s41401-023-01198-0

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