1. Academic Validation
  2. Blunting TRPML1 channels protects myocardial ischemia/reperfusion injury by restoring impaired cardiomyocyte autophagy

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

  • Basic Res Cardiol. 2022 Apr 7;117(1):20. doi: 10.1007/s00395-022-00930-x.
Yanhong Xing  # 1 Zhongheng Sui  # 1 Yucheng Liu  # 1 Meng-Meng Wang  # 2 Xiangqing Wei 3 Qixia Lu 1 Xinyan Wang 1 Nan Liu 1 Chen Lu 1 Rong Chen 1 Mengmei Wu 1 Yuqing Wang 4 Yu-Hong Zhao 5 Feng Guo 6 Jun-Li Cao 7 Jiansong Qi 8 9 Wuyang Wang 10
Affiliations

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.
  • 2 Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital, China Medical University, Shenyang, 110122, Liaoning, China.
  • 3 Department of Anesthesiology, the Second Affiliated Hospital of Nantong University, Nantong, 226006, Jiangsu, China.
  • 4 Department of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu University, Fukuoka, Kyushu, 8128582, Japan.
  • 5 Department of Clinical Epidemiology, Clinical Research Center, Shengjing Hospital of China Medical University, No. 36 San Hao Street, Shenyang, 110004, Liaoning, China.
  • 6 Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, Liaoning, China. blueforest611@hotmail.com.
  • 7 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. caojl0310@aliyun.com.
  • 8 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. maggie.qi@dal.ca.
  • 9 Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2, Canada. maggie.qi@dal.ca.
  • 10 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. wuyangwang80@gmail.com.
  • # Contributed equally.
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.

Keywords

Autophagy inhibition; Cardiomyocyte death; Ischemia/reperfusion injury; Mitochondria turnover.

Figures
Products