TY - JOUR
T1 - Blunting TRPML1 channels protects myocardial ischemia/reperfusion injury by restoring impaired cardiomyocyte autophagy
AU - Xing, Yanhong
AU - Sui, Zhongheng
AU - Liu, Yucheng
AU - Wang, Meng meng
AU - Wei, Xiangqing
AU - Lu, Qixia
AU - Wang, Xinyan
AU - Liu, Nan
AU - Lu, Chen
AU - Chen, Rong
AU - Wu, Mengmei
AU - Wang, Yuqing
AU - Zhao, Yu hong
AU - Guo, Feng
AU - Cao, Jun li
AU - Qi, Jiansong
AU - Wang, Wuyang
N1 - Funding Information:
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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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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U2 - 10.1007/s00395-022-00930-x
DO - 10.1007/s00395-022-00930-x
M3 - Article
C2 - 35389129
AN - SCOPUS:85128086276
SN - 0300-8428
VL - 117
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 1
M1 - 20
ER -