Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury

Objectives Determine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity. Background ApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF). Methods In the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic ( ApomTG ), ApoM knockout ( ApomKO ), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls. Results ApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients. ApomTG mice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass. ApomTG attenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH. Conclusions ApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy. Highlights ### Competing Interest Statement AJ has a pending patent for fusion protein nanodiscs for the treatment of heart failure and eye diseases and receives research funding from AstraZeneca. NOS has received consulting fees from Sension Therapeutics and investigator-initiated research funding from Regeneron Pharmaceuticals unrelated to the content of this study. * ApoM : apolipoprotein M ApoA-I : apolipoprotein A-I HDL : high-density lipoprotein HF : heart failure LAMP1 : lysosomal associated membrane protein 1 LVEF : left ventricular ejection fraction S1P : sphingosine-1-phosphate S1PR3 : S1P receptor 3 TFEB : transcription factor EB