Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury

Abstract

Apolipoprotein M (ApoM) is an apolipoprotein that binds sphingosine-1-phosphate (S1P) and high-density lipoprotein. ApoM, via S1P signaling, is thought to protect cardiomyocytes from apoptosis, and ApoM plasma protein levels are inversely associated with increased mortality risk in human heart failure. Here, using a doxorubicin cardiotoxicity model, we identify ApoM as a novel regulator of myocardial autophagy. Doxorubicin treatment reduces ApoM plasma protein levels in wild-type mice and humans. Hepatic ApoM transgenic overexpression (ApomTG) protects mice from reductions in cardiac function observed in littermate controls. Though ApoM did not alter markers of DNA damage, apoptosis, Akt signaling, or fibrosis, ApoM prevented doxorubicin-induced reductions in autophagic flux. In the murine myocardium, doxorubicin reduced the nuclear protein content of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, in control mice but not ApomTG mice. Furthermore, adeno-associated virus 9 mediated knockdown of TFEB reversed the beneficial effects of ApoM on the myocardium, leading to cardiomyopathy and mortality in ApomTG mice. Our studies provide a mechanistic link between ApoM and the autophagy-lysosome pathway in the murine heart. Our clinical observations that reduced ApoM is associated with mortality may be explained by its role in sustaining autophagy.One sentence summaryApolipoprotein M attenuates doxorubicin cardiotoxicity by preserving nuclear translocation of TFEB and autophagic flux.

Endothelial Spns2 and ApoM Regulation of Vascular Tone and Hypertension Via Sphingosine‐1‐Phosphate

“… 23 A recent study revealed a cardioprotective role of ApoM‐bound S1P via myocardial autophagy. 68 Altogether, published and current findings of this study suggest that S1P signaling can protect the heart from pathological hypertrophy by different means.…”