Doxorubicin-Induced Cardiotoxicity Through SIRT1 Loss Potentiates Overproduction of Exosomes in Cardiomyocytes.

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.