Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury

Zhen Guo; Carla Valenzuela Ripoll; Antonino Picataggi; David R Rawnsley; Mualla Ozcan; Julio A Chirinos; Ezhilarasi Chendamarai; Amanda Girardi; Terrence Riehl; Hosannah Evie; Ahmed Diab; Attila Kovacs; Krzysztof Hyrc; Xiucui Ma; Aarti Asnani; Swapnil V Shewale; Marielle Scherrer-Crosbie; Lauren Ashley Cowart; John S Parks; Lei Zhao; David Gordon; Francisco Ramirez-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

doi:10.1016/j.jacbts.2022.09.010

Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury

JACC Basic Transl Sci. 2023 Jan 4;8(3):340-355. doi: 10.1016/j.jacbts.2022.09.010. eCollection 2023 Mar.

Authors

Zhen Guo¹, Carla Valenzuela Ripoll¹, Antonino Picataggi¹, David R Rawnsley¹, Mualla Ozcan¹, Julio A Chirinos², Ezhilarasi Chendamarai¹, Amanda Girardi¹, Terrence Riehl¹, Hosannah Evie¹, Ahmed Diab¹, Attila Kovacs¹, Krzysztof Hyrc³, Xiucui Ma^{1

4}, Aarti Asnani⁵, Swapnil V Shewale², Marielle Scherrer-Crosbie², Lauren Ashley Cowart^{6

7}, John S Parks⁸, Lei Zhao⁹, David Gordon⁹, Francisco Ramirez-Valle⁹, Kenneth B Margulies², Thomas P Cappola², Ankit A Desai¹⁰, Lauren N Pedersen¹, Carmen Bergom¹, Nathan O Stitziel¹, Michael P Rettig¹, John F DiPersio¹, Stefan Hajny^{11

12}, Christina Christoffersen^{11

12}, Abhinav Diwan^{1

4}, Ali Javaheri¹

Affiliations

¹ Washington University School of Medicine, St Louis, Missouri, USA.
² Perelman School of Medicine, University of Pennsylvania School of Medicine/Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Hope Center, Washington University School of Medicine, St Louis, Missouri, USA.
⁴ John Cochran Veterans Affairs Medical Center, St Louis, Missouri, USA.
⁵ Beth Israel Deaconess, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Virginia Commonwealth University, Richmond, Virginia, USA.
⁷ Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA.
⁸ Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁹ Bristol Myers Squibb, Princeton, New Jersey, USA.
¹⁰ Indiana University, Indianapolis, Indiana, USA.
¹¹ Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹² Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.

Keywords: TFEB; anthracycline; apolipoprotein M; autophagy; cardiomyopathy.

Abstract

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