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Clin Sci (Lond). 2019 Jul 15;133(13):1505-1521. doi: 10.1042/CS20181022. Print 2019 Jul 15.

Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.

Author information

1
Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
2
Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, Canada N6A 4S2.
3
Departments of Medicine and Pathology and Laboratory Medicine, Western University, London, ON, Canada N6A 4S2.
4
Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8.
5
Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, U.S.A.
6
Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China tqpeng@suda.edu.cn.

Abstract

Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.

KEYWORDS:

Autolysosomes; Autophagic flux; Doxorubicin cardiotoxicity; Nicotinamide riboside; sirtuins

PMID:
31266854
DOI:
10.1042/CS20181022

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