2. Academic Validation
  3. Doxorubicin downregulates autophagy to promote apoptosis-induced dilated cardiomyopathy via regulating the AMPK/mTOR pathway

Doxorubicin downregulates autophagy to promote apoptosis-induced dilated cardiomyopathy via regulating the AMPK/mTOR pathway

  • Biomed Pharmacother. 2023 Apr 13;162:114691. doi: 10.1016/j.biopha.2023.114691.
Sheng Zhang 1,  Xueping Wei 2,  Haijin Zhang 2,  Youping Wu 3,  Junsong Jing 2,  Rongrong Huang 2,  Ting Zhou 4,  Jingjin Hu 2,  Yueguo Wu 5,  Yuanyuan Li 6,  Zhenqiang You 7
Affiliations

Affiliations

  • 1 Center for Safety Evaluation and Research, Hangzhou Medical College, Hangzhou, China.
  • 2 School of Public Health, Hangzhou Medical College, Hangzhou, China.
  • 3 The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
  • 4 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China.
  • 5 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China. Electronic address: wyg2004126@163.com.
  • 6 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China. Electronic address: lyy3207@163.com.
  • 7 School of Public Health, Hangzhou Medical College, Hangzhou, China. Electronic address: youzq1979@163.com.
PMID: 37060659 DOI: 10.1016/j.biopha.2023.114691
Abstract

The broad-spectrum antineoplastic drug doxorubicin (DOX) has one of the most serious chronic side effects on the heart, dilated cardiomyopathy, but the precise molecular mechanisms underlying disease progression subsequent to long latency periods remain puzzling. Here, we established a model of DOX-induced dilated cardiomyopathy. In a cardiac cytology exploration, we found that differentially expressed genes in the KEGG signaling pathway enrichment provided a novel complex network of mTOR bridging Autophagy and oxidative stress. Validation results showed that DOX caused intracellular Reactive Oxygen Species accumulation in cardiomyocytes, disrupted mitochondria, led to imbalanced intracellular energy metabolism, and triggered cardiomyocyte Apoptosis. Apoptosis showed a negative correlation with DOX-regulated cardiomyocyte Autophagy. To evaluate whether the inhibition of mTOR could upregulate Autophagy to protect cardiomyocytes, we used rapamycin to restore Autophagy depressed by DOX. Rapamycin increased cardiomyocyte survival by easing the autophagic flux blocked by DOX. In addition, rapamycin reduced oxidative stress, prevented mitochondrial damage, and restored energy metabolic homeostasis in DOX-treated cardiomyocytes. In vivo, we used metformin (Met) which is an AMPK Activator to protect cardiac tissue to alleviate DOX-induced dilated cardiomyopathy. In this study, Met significantly attenuated the oxidative stress response of myocardial tissue caused by DOX and activated cardiomyocyte Autophagy to maintain cardiomyocyte energy metabolism and reduce cardiomyocyte Apoptosis by downregulating mTOR activity. Overall, our study revealed the role of Autophagy and Apoptosis in DOX-induced dilated cardiomyopathy and demonstrated the potential role of regulation of the AMPK/mTOR axis in the treatment of DOX-induced dilated cardiomyopathy.

Keywords

AMPK; Apoptosis; Autophagy; Dilated cardiomyopathy; Doxorubicin; MTOR.

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