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Doxorubicin-Induced Cardiotoxicity Through SIRT1 Loss Potentiates Overproduction of Exosomes in Cardiomyocytes
Shuai Zhang1, Yu Yang1, Xinchen Lv1
1Department of Forensic Medicine, School of Basic Medicine, Soochow University, Suzhou 215123, China.
Abstract:
Mutual interaction between doxorubicin (DOX) and cardiomyocytes is crucial for cardiotoxicity progression. Cardiomyocyte injury is an important pathological feature of DOX-induced cardiomyopathy, and its molecular pathogenesis is multifaceted. In addition to the direct toxic effects of DOX on cardiomyocytes, DOX-induced exosomes in the extracellular microenvironment also regulate the pathophysiological states of cardiomyocytes. However, the mechanisms by which DOX regulates exosome secretion and subsequent pathogenesis remain incompletely understood. Here, we found that DOX significantly increased exosome secretion from cardiomyocytes, and inhibiting this release could alleviate cardiomyocyte injury. DOX promoted exosome secretion by reducing cardiomyocyte silencing information regulator 1 (SIRT1) expression, exacerbating cardiotoxicity. DOX impaired lysosomal acidification in cardiomyocytes, reducing the degradation of intracellular multivesicular bodies (MVBs), resulting in an increase in MVB volume before fusing with the plasma membrane to release their contents. Mechanistically, SIRT1 loss inhibited lysosomal acidification by reducing the expression of the ATP6V1A subunit of the lysosomal vacuolar-type H+ ATPase (V-ATPase) proton pump. Overexpressing SIRT1 increased ATP6V1A expression, improved lysosomal acidification, inhibited exosome secretion, and thereby alleviated DOX-induced cardiotoxicity. Interestingly, DOX also induced mitochondrial-derived vesicle formation in cardiomyocytes, which may further increase the abundance of MVBs and promote exosome release. Collectively, this study identified SIRT1-mediated impairment of lysosomal acidification as a key mechanism underlying the increased exosome secretion from cardiomyocytes induced by DOX, providing new insights into DOX-induced cardiotoxicity pathogenesis.
Insights
Doxorubicin (DOX) increases cardiotoxicity by promoting exosome secretion from cardiomyocytes via reduced SIRT1 expression and impaired lysosomal acidification. Restoring SIRT1 alleviates DOX-induced cardiomyocyte injury.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Doxorubicin (DOX) induces cardiotoxicity, a significant clinical concern.
- Cardiomyocyte injury is a key pathological feature of DOX-induced cardiomyopathy.
- DOX-induced exosomes contribute to cardiotoxicity, but mechanisms of secretion regulation are unclear.
Purpose of the Study:
- To elucidate the mechanisms by which DOX regulates exosome secretion from cardiomyocytes.
- To investigate the role of SIRT1 and lysosomal acidification in DOX-induced cardiotoxicity.
- To identify potential therapeutic targets for mitigating DOX cardiotoxicity.
Main Methods:
- Investigated DOX effects on exosome secretion in cardiomyocytes.
- Assessed the role of silencing information regulator 1 (SIRT1) and lysosomal acidification.
- Utilized molecular biology techniques including gene overexpression and assessment of lysosomal function.
- Examined the expression of ATP6V1A subunit of vacuolar-type H+ ATPase (V-ATPase).
Main Results:
- DOX significantly increased exosome secretion from cardiomyocytes, exacerbating injury.
- DOX reduced SIRT1 expression, impairing lysosomal acidification and multivesicular body (MVB) degradation.
- SIRT1 loss decreased ATP6V1A expression, inhibiting V-ATPase function.
- Overexpressing SIRT1 improved lysosomal acidification, reduced exosome secretion, and alleviated DOX cardiotoxicity.
Conclusions:
- SIRT1-mediated impairment of lysosomal acidification is a key mechanism for increased DOX-induced exosome secretion.
- Targeting SIRT1 and lysosomal acidification offers a novel therapeutic strategy for DOX cardiotoxicity.
- DOX-induced mitochondrial-derived vesicles may also contribute to increased exosome release.
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