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. 2021 May 28;128(11):1629-1641.
doi: 10.1161/CIRCRESAHA.120.317046. Epub 2021 Apr 22.

NAD+ Repletion Reverses Heart Failure With Preserved Ejection Fraction

Dan Tong  1 , Gabriele G Schiattarella  1 , Nan Jiang  1 , Francisco Altamirano  1 , Pamela A Szweda  1 , Abdallah Elnwasany  1 , Dong I Lee  2 , Heesoo Yoo  1 , David A Kass  2 , Luke I Szweda  1 , Sergio Lavandero  1   3 , Eric Verdin  4 , Thomas G Gillette  1 , Joseph A Hill  1   5
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NAD+ Repletion Reverses Heart Failure With Preserved Ejection Fraction (V体育2025版)

Dan Tong et al. Circ Res. .

Abstract

[Figure: see text].

Keywords: NAD; acetylation; cardiomyopathy; heart failure; mitochondria. VSports手机版.

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Figures

Figure 1.
Figure 1.. Mitochondrial Morphological and Functional Changes in HFpEF Hearts
(A) Representative electron microscopy images of cardiac tissue isolated from control and HFpEF mice. Scale bar = 1 μm. (B) Schematized image depicting mitochondrial metabolic pathways. (C) Oxygen consumption rates (OCR) of isolated mitochondria exposed to palmitoylcarnitine as substrate. State 2 is the basal level, state 3 is the maximal level after adding ADP, and state 4 is the level after ADP exhaustion. N=4 mice in each group. (D) OCR of isolated mitochondria exposed to pyruvate as substrate. State 2 is the basal level, state 3 is the maximal level after adding ADP, and state 4 is the level after ADP exhaustion. N=4 mice in each group. (E) OCR of isolated mitochondria exposed to glutamate as substrate. State 2 is the basal level, state 3 is the maximal level after adding ADP, and state 4 is the level after ADP exhaustion. N=4 mice in each group. (F) OCR of permeabilized adult mouse ventricular myocytes (AMVM) exposed to palmitoylcarnitine as substrate. State 4o is the level after adding oligomycin 1μM. N=6 mice in each group. Each point is the average of 2 experiments from each mouse. (G) OCR of permeabilized AMVM exposed to pyruvate as substrate. State 4o is the level after adding oligomycin 1μM. N=5 mice in each group. Each point is the average of 2 experiments from each mouse. (H) OCR of permeabilized AMVM exposed to glutamate as substrate. State 4o is the level after adding oligomycin 1μM. N= 6 mice in each group. Each point is the average of 2 experiments from each mouse. (I) OCR of permeabilized AMVM exposed to succinate as substrate. State 4o is the level after adding oligomycin 1μM. N=6 mice in chow group, and N= 5 in HFpEF group Two-way ANOVA followed by Sidak’s multiple comparisons test for all experiments.
Figure 2.
Figure 2.. Protein Hyperacetylation-mediated FAO Suppression
(A) ACAD activity using C16 palmitoylCoA as substrate. Values were normalized to the Chow group. N=4 tests from 4 mice in each group. Kruskal-Wallis test with Dunn’s multiple comparisons test. (B) ACAD activity using C8 OctanoylCoA as substrate. Values were normalized to the Chow group. N=4 tests from 4 mice in each group. Kruskal-Wallis test with Dunn’s multiple comparisons test. (C) Immunoblot image of acetylated proteins in the mitochondrial fraction isolated from left ventricle (LV) of control and HFpEF mice. Tom20 was used as loading controls. (D) Densitometric analysis ratio between total acetylated protein and Tom20. Values were normalized to the Chow group. N= 6 tests from 6 mice in each group. Mann-Whitney test. (E) Immunoblot image of acetylated proteins in the mitochondrial fraction isolated from left ventricle (LV) of control, HFpEF, HFD alone, and L-NAME alone mice. VDAC was used as loading controls. (F) Densitometric analysis ratio between total acetylated protein and VDAC. Values were normalized to the Chow group. N=8 mice in chow and HFpEF groups, and N=4 for HFD and L-NAME groups. Kruskal-Wallis test with Dunn’s multiple comparisons test (G) Representative image of immunoprecipitate using anti-acetylated lysine antibody and probed with anti-VLCAD, HADHA and VDAC antibodies. (H) Ratio of acetylated protein to total protein. N=4 tests from 4 mice for each group. Kruskal-Wallis test with Dunn’s multiple comparisons test
Figure 3.
Figure 3.. Impaired Sirt3 Levels and NAD+ Bioavailability in HFpEF Hearts
(A) Representative immunoblot image of Sirt3, GCN5L1 and Tom20 protein abundance in mitochondria fraction isolated from LV tissue of control, HFpEF, HFD alone, and L-NAME alone mice. (B) Densitometric analysis ratio between Sirt3 and Tom20. Values were normalized to the Chow group. N=9 mice in chow and HFpEF groups, and N=4 for HFD and L-NAME groups. Kruskal-Wallis test with Dunn’s multiple comparisons test (C) E/E’ measured by tissue Doppler echocardiography in Sirt3 fl+/+, αMHC Cre-(Flox mice), Sirt3 fl+/+, αMHC Cre+ (KO mice), and Sirt3 fl−/−, αMHC Cre+ (Cre mice) fed by HFD+L-NAME for 7-8 weeks. N = 6, 6, and 3 mice in each group. Kruskal-Wallis test with Dunn’s multiple comparisons test (D) Nampt mRNA level in LV tissue of control, HFpEF, HFD alone, and L-NAME alone mice, normalized to 18s. N=9 mice in chow and HFpEF groups, and =6 for HFD and L-NAME groups. One-way ANOVA followed by Tukey’s multiple comparisons test. (E) NAD+ level in LV tissue of control and HFpEF mice. N=6 and 5 in control and HFpEF group. Mann-Whitney test. (F) mRNA levels of Nampt in human myocardial biopsies from non-failing (NoHF), HFrEF and HFpEF subjects. N=15 subjects each in nonHF and HFrEF group, n=12 subjects in HFpEF group). One-way ANOVA followed by Tukey’s multiple comparisons test. (G) Schematic depicting the NAD+ salvage pathway and its relationship with sirtuins.
Figure 4.
Figure 4.. NAD+ Repletion Improved Mitochondrial Function and Reversed HFpEF Phenotype
(A) Schematic depicting the experimental design of nicotinamide riboside (NR) vs placebo treatment. (B) NAD+ level in LV tissue of control mice (Chow), HFpEF mice treated with placebo (HFpEF+Pl) vs NR (HFpEF+NR). N= 5, 5, 4 mice in each group, respectively. Kruskal-Wallis test with Dunn’s multiple comparisons test. (C) Representative image of immunoprecipitate using anti-acetylated lysine antibody and probed with anti-VLCAD and HADHA antibodies. (D) OCR of isolated mitochondria using palmitoylcarnitine as substrate from control mice, HFpEF mice treated with placebo vs NR. N=7,6, 4 mice for each group. Two-way ANOVA followed by Sidak’s multiple comparisons test. (E) Ratio of heart weight (HW) to tibia length (TL) from control mice, HFpEF mice treated with placebo vs NR. N = 4, 5, 4 in each group. Results of Kruskal-Wallis test with Dunn’s multiple comparisons test depicted in figure (results of one-way ANOVA followed by Tukey’s multiple comparisons test: Chow vs HFpEF+Pl, p=9.0x10−7; HFpEF+Pl vs HFpEF+NR, p=0.00052; Chow vs HFpEF+NR, p=0.00046). (F) Ratio between mitral E wave and E’ wave (E/E’). N = 7, 10, 10 mice in each group. One-way ANOVA followed by Tukey’s multiple comparisons test. (G) Running distance during exercise exhaustion test. N = 10, 10, 13 mice per group. One-way ANOVA followed by Tukey’s multiple comparisons test. (H) Ratio between lung water (subtraction between wet and dry lung weight) and TL. N= 4, 6, 4 mice per group. Kruskal-Wallis test with Dunn’s multiple comparisons test. (I) Schematic depicting the experimental design of P7C3-A20 vs placebo treatment. (J) NAD+ level in LV tissue of control mice (Chow), HFpEF mice treated with placebo (HFpEF+Pl) vs P7C3-A20 (HFpEF+P7C3). N=3 from 3 mice in each group. Results of Kruskal-Wallis test with Dunn’s multiple comparisons test depicted in figure (results of one-way ANOVA followed by Tukey’s multiple comparisons test: Chow vs HFpEF+Pl, p=0.0074; HFpEF+Pl vs HFpEF+P7C3, p 0.031; Chow vs HFpEF+P7C3, p=0.45). (K) Ratio between mitral E wave and E’ wave (E/E’). N = 6,4,6 mice per group. Results of Kruskal-Wallis test with Dunn’s multiple comparisons test depicted in figure (results of one-way ANOVA followed by Tukey’s multiple comparisons test: Chow vs HFpEF+Pl, p=6.8x10−5; HFpEF+Pl vs HFpEF+P7C3, p=0.0053; Chow vs HFpEF+P7C3, p=0.036).
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"V体育2025版" References

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