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

Figures

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  Figure 1. Body−weight dynamics. 1—drug administration endpoint for control, DOX, and NR+DOX groups; 2—drug administration endpoint for NR/NR+DOX group. The first weighing was carried out before the start of each manipulation. During the drug administration, the animals were weighed every 2 days on the day of the substance administration (9 times). At the end of the administration in NR/NR+DOX group, the weight and clinical condition of the animals were monitored once a week. */*—p < 0.05, **—p < 0.01, and ***—p < 0.001 which shows significant difference compared to control group (*—DOX; *—NR+DOX). Data are presented as median [25%; 75%]. Control represents control group (n = 15); DOX represents doxorubicin group (n = 15); NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode (n = 15); and NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode (n = 15).

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  Figure 2. Treadmill activity duration. */*—p < 0.05 compared to the initial value (start of the experiment) (*—DOX; *—NR+DOX). Data are presented as median [25%; 75%]. Control represents control group (n = 15); DOX represents doxorubicin group (n = 15); NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode (n = 15); and NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode (n = 15).

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  Figure 3. Left-ventricular parameters according to ECHO. (A)—left-ventricular end-systolic internal diameter, or LVIDs; (B)—left-ventricular end-diastolic internal diameter, or LVIDd; (C)—fractional shortening, or FS; (D)—anterior wall thickness, or IVS; and (E)—posterior wall thickness, or LVPW. */*/*—significant difference compared to the start of the experiment (*—DOX; *—NR+DOX; and *—NR/NR+DOX); #/#/#—significant difference in FS between DOX, NR+DOX, and NR/NR+DOX groups compared to control group; and #/#/#—significant difference in LVIDs and LVIDd between control, DOX, and NR+DOX groups compared to NR/NR+DOX group (#—DOX; #—NR+DOX; and #—NR/NR+DOX). (*/*/*—p < 0.05, **/**/**—p < 0.01, and ***/***/***—p < 0.001; #/#/#—p < 0.05, ##/##—p < 0.01, and ###—p < 0.001.) Data are presented as median [25%; 75%]. Control represents control group (n = 15); DOX represents doxorubicin group (n = 15); NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode (n = 15); NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode (n = 15).

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  Figure 4. Representative ECHO photographs of control, DOX, NR+DOX, and NR/NR+DOX groups at the start of the experiment and two months after doxorubicin administration completion. (A,B)—control group; (C,D)—DOX group; (E,F)—NR+DOX group; and (G,H)—NR/NR+DOX group. DOX represents doxorubicin group; NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode; and NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode.

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  Figure 5. Cardiac muscle tissue. (A)—control group, normal structure. (B)—DOX group, dystrophic changes in cardiomyocytes: loss of striation (1,2 arrows) and vacuolization of the cytoplasm (stars). (C)—NR+DOX group, minimal alterative changes. (D)—NR/NR+DOX group, minimal alterative changes. Stained with hematoxylin–eosin, ×50. DOX represents doxorubicin group; NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode; and NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode.

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  Figure 6. Morphometric values (% area of collagen fibers) in cardiac muscle. (A,B)—interstitial fibrosis; (C,D)—perivascular fibrosis; (E,F)—epicardial fibrosis. Collagen fibers are blue. Staining by Mallory, × 100. *—p < 0.05, **—p < 0.01, and ***—p < 0.001. Data are presented as median [25%; 75%]. Control represents control group (n = 15); DOX represents doxorubicin group (n = 15); NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode (n = 15); and NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode (n = 15).

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  Figure 7. Mesenteric artery functional activity. (A)—dose-dependent response curves to phenylephrine (PE); (B)—dose−dependent response curves to acetylcholine (ACh); (C)—area under the curves (AUC) for PE-dependent response; and (D)—AUC for ACh-dependent response. *—p < 0.05, and ***—p < 0.001, significant difference compared to control group. Values represent mean ± SEM mean from 9 arteries of 3 rats in every group (n = 36). Control represents control group; DOX represents doxorubicin group; NR+DOX represents nicotinamide riboside + doxorubicin group—combined mode; and NR/NR+DOX represents nicotinamide riboside/nicotinamide riboside + doxorubicin group—preventive mode.

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  Figure 8. Experimental design.