Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure
Bo Zhou, … , Kevin D. O’Brien, Rong Tian
Bo Zhou, … , Kevin D. O’Brien, Rong Tian
Published August 13, 2020
Citation Information: J Clin Invest. 2020;130(11):6054-6063. https://doi.org/10.1172/JCI138538.
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Clinical Research and Public Health Cardiology Inflammation Article has an altmetric score of 146

Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Abstract

BACKGROUND While mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level.METHODS We compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage–associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor.RESULTS We demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.CONCLUSION These findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF.TRIAL REGISTRATION ClinicalTrials.gov NCT03727646.FUNDING This study was funded by the NIH, the University of Washington, and the American Heart Association.

Authors

Bo Zhou, Dennis Ding-Hwa Wang, Yanhua Qiu, Sophia Airhart, Yaxin Liu, April Stempien-Otero, Kevin D. O’Brien, Rong Tian

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Figure 3

Secreted IL-6 from MitoDAMP stimulation impairs mitochondrial respiration by reducing complex I activity.

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Secreted IL-6 from MitoDAMP stimulation impairs mitochondrial respiratio...
(A) Secreted IL-6 protein level by ELISA of healthy PBMCs after 2-hour (n = 3) or 4-hour (n = 6) treatment of vehicle or MitoDAMP. P value determined by paired 2-tailed t test. (B) Maximal respiration of healthy PBMCs after 4-hour treatments of vehicle or MitoDAMP with or without 100 μM LMT28, a specific inhibitor of the IL-6 receptor b (GP 130). n = 4. (C) Maximal respiration of healthy PBMCs after 4-hour treatments of vehicle or increasing concentrations of human recombinant IL-6. n = 4. B and C analyzed with 1-way ANOVA with multiple pairwise comparisons. (D) Representative Seahorse plot of baseline and post-drug treatment OCR of healthy PBMCs after 4-hour treatments of vehicle or IL-6 (1 ng/mL). FCCP; uncoupling agent by permeabilizing inner mitochondrial membrane; Rotenone (Rot): complex I inhibitor; Antimycin A (AA): complex III inhibitor; TMPD/Ascorbate: exogenous electron donor for complex IV. n = 3. (E) Quantitation of D. (F) Complex I activity of healthy PBMCs after 4-hour treatments of vehicle or IL-6 (1 ng/mL). n = 5. Vehicle normalized to 1. E and F analyzed by paired 2-tailed t test. All data shown in mean ± SEM.