Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury
Zhen Guo, Carla Valenzuela Ripoll, Antonino Picataggi, David R. Rawnsley, Mualla Özcan, Julio A. Chirinos, Ezhilarasi Chendamarai, Amanda Girardi, Terrence E. Riehl, Hosannah Evie, Ahmed Diab, Attila Kovács, Krzysztof Hyrc, Xiucui Ma, Aarti Asnani, Swapnil V. Shewale, Marielle Scherrer‐Crosbie, L. Ashley Cowart, John S. Parks, Lei Zhao, David Gordon, Francisco Ramírez‐Valle, Kenneth B. Margulies, Thomas P. Cappola, Ankit A. Desai, Lauren N. Pedersen, Carmen Bergom, Nathan O. Stitziel, Michael P. Rettig, John F. DiPersio, Stefan Hajny, Christina Christoffersen, Abhinav Diwan, Ali Javaheri
Abstract
Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury.