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Blunting TRPML1 channels protects myocardial ischemia/reperfusion injury by restoring impaired cardiomyocyte autophagy

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Abstract

Accumulating evidence suggests that autophagy dysfunction plays a critical role in myocardial ischemia/reperfusion (I/R) injury. However, the underling mechanism of malfunctional autophagy in the cardiomyocytes subjected to I/R has not been well defined. As a result, there is no effective therapeutic option by targeting autophagy to prevent myocardial I/R injury. Here, we used both an in vitro and an in vivo I/R model to monitor autophagic flux in the cardiomyocytes, by exposing neonatal rat ventricular myocytes to hypoxia/reoxygenation and by subjecting mice to I/R, respectively. We observed that the autophagic flux in the cardiomyocytes subjected to I/R was blocked in both in vitro and in vivo models. Down-regulating a lysosomal cationic channel, TRPML1, markedly restored the blocked myocardial autophagic flux induced by I/R, demonstrating that TRPML1 directly contributes to the blocked autophagic flux in the cardiomyocytes subjected to I/R. Mechanistically, TRPML1 is activated secondary to ROS elevation following ischemia/reperfusion, which in turn induces the release of lysosomal zinc into the cytosol and ultimately blocks the autophagic flux in cardiomyocytes, presumably by disrupting the fusion between autophagosomes and lysosomes. As a result, the inhibited myocardial autophagic flux induced by TRPML1 disrupted mitochondria turnover and resulted in mass accumulation of damaged mitochondria and further ROS release, which directly led to cardiomyocyte death. More importantly, pharmacological and genetic inhibition of TRPML1 channels greatly reduced infarct size and rescued heart function in mice subjected to I/R in vivo by restoring impaired myocardial autophagy. In summary, our study demonstrates that secondary to ROS elevation, activation of TRPML1 results in autophagy inhibition in the cardiomyocytes subjected to I/R, which directly leads to cardiomyocyte death by disrupting mitochondria turnover. Therefore, targeting TRPML1 represents a novel therapeutic strategy to protect against myocardial I/R injury.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (NSFC) Grants (81772559 to W. W; 82101314 to Y. X; 81600967 to C. L; 81971212 to F. G), NSF grants of the Jiangsu Province (BK20170262 to W. W), Key University Science Research Project of Jiangsu Province (20KJA310001 to W.W), Jiangsu Specially-Appointed Professor award to W.W, Jiangsu Province Innovative and Entrepreneurial Talent program to W.W and Jiangsu Province Innovative and Entrepreneurial Team program to W.W. Natural Science Foundation of Liaoning Province (2021-MS-161 to M.M. W.). We are grateful to Dr. Hailey Jansen (Libin Cardiovascular Institute, University of Calgary, Canada) for critical reading through the manuscript and appreciate the encouragement and helpful comments from other members of the Wang laboratory.

Author information

Author notes

  1. Yanhong Xing, Zhongheng Sui, Yucheng Liu and Meng-meng Wang contribute equally.

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, 221004, Jiangsu, China

    Yanhong Xing, Zhongheng Sui, Yucheng Liu, Qixia Lu, Xinyan Wang, Nan Liu, Chen Lu, Rong Chen, Mengmei Wu, Jun-li Cao, Jiansong Qi & Wuyang Wang

  2. Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital, China Medical University, Shenyang, 110122, Liaoning, China

    Meng-meng Wang

  3. Department of Anesthesiology, the Second Affiliated Hospital of Nantong University, Nantong, 226006, Jiangsu, China

    Xiangqing Wei

  4. Department of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu University, Fukuoka, Kyushu, 8128582, Japan

    Yuqing Wang

  5. Department of Clinical Epidemiology, Clinical Research Center, Shengjing Hospital of China Medical University, No. 36 San Hao Street, Shenyang, 110004, Liaoning, China

    Yu-hong Zhao

  6. Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning, China

    Feng Guo

  7. Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada

    Jiansong Qi

Authors
  1. Yanhong Xing
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  2. Zhongheng Sui
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  3. Yucheng Liu
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  4. Meng-meng Wang
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  5. Xiangqing Wei
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  6. Qixia Lu
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  7. Xinyan Wang
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  8. Nan Liu
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  9. Chen Lu
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  10. Rong Chen
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  11. Mengmei Wu
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  12. Yuqing Wang
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  13. Yu-hong Zhao
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  14. Feng Guo
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  15. Jun-li Cao
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  16. Jiansong Qi
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  17. Wuyang Wang
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Contributions

WW and JQ conceived of the presented idea. YX, ZS, LY, MW, XW, QL, NL, CL, RC, MW, YW, YHZ, FG, and JQ performed experiments and contributed to the interpretation of the results. WW, JQ, FG and JLC supervised the findings of this work. WW and JQ wrote the manuscript. All authors discussed the results and contributed to the final manuscript.

Corresponding authors

Correspondence to Feng Guo, Jun-li Cao, Jiansong Qi or Wuyang Wang.

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Conflict of interests

The authors disclose no competing interests.

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Xing, Y., Sui, Z., Liu, Y. et al. Blunting TRPML1 channels protects myocardial ischemia/reperfusion injury by restoring impaired cardiomyocyte autophagy. Basic Res Cardiol 117, 20 (2022). https://doi.org/10.1007/s00395-022-00930-x

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  • DOI: https://doi.org/10.1007/s00395-022-00930-x

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