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Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy.

ABSTRACT: Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature male SPF Wistar rats. The animals were randomized into four groups (a control group and three experimental groups) which determined the doxorubicin (intraperitoneally) and NR (intravenous) doses as well as the specific modes of NR administration (combined, preventive). We demonstrated the protective effect of NR on the cardiovascular system both with combined and preventive intravenous drug administration, which was reflected in a fibrous tissue formation decrease, reduced fractional-shortening decrease, and better antioxidant system performance. At the same time, it is important to note that the preventive administration of NR had a more significant protective effect on the animal organism as a whole. This was confirmed by better physical activity parameters and vascular bed conditions. Thus, the data obtained during the study can be used for further investigation into chronic doxorubicin-induced cardiomyopathy prevention and treatment approaches.

SUBMITTER: Podyacheva E

PROVIDER: S-EPMC9653852 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy.

Podyacheva Ekaterina E N Yu Natalia N V A Vsevolod V Mukhametdinova Daria D Goncharova Irina I Zelinskaya Irina I Sviridov Eric E Martynov Michael M Osipova Svetlana S Toropova Yana Y

International journal of molecular sciences 20221028 21

Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature ...[more]

PMID: 36361882

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Project description:BackgroundMyocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD+) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD+ in the failing heart.MethodsTo explore possible alterations of NAD+ homeostasis in the failing heart, we quantified the expression of NAD+ biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRFHKO) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD+ precursor supplementation on cardiac function in both mouse models.ResultsWe observed a 30% loss in levels of NAD+ in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the Nmrk2 gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD+ depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD+ synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD+ levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment.ConclusionsThe data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.

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Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy.

Publications

Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy.

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