Nicotinamide Mononucleotide, an Intermediate of NAD+ Synthesis, Protects the Heart from Ischemia and Reperfusion

Yamamoto, Takanobu; Byun, Jaemin; Zhai, Peiyong; Ikeda, Yoshiyuki; Oka, Shinichi; Sadoshima, Junichi

doi:10.1371/journal.pone.0098972

Cited by 254 publications

(226 citation statements)

References 28 publications

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“…Activation of SIRT1 by resveratrol attenuates cardiac I/R injury by increasing ERK phosphorylation and reducing p38 and JNK expression levels (19). Furthermore, exogenous application of nicotinamide mononucleotide protects heart from I/R by mimicking the cardioprotective effect of ischemic preconditioning and overexpression of NAMPT, thereby protecting through an SIRT1-dependent mechanism (202). In contrast, in cardiac myocytes, the autophagic flux is impaired by NAMPT downregulation, probably acting in concert with SIRT1 signaling pathway (69).…”

Section: (K143) Residuesmentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

295

238

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Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

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Section: (K143) Residuesmentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

295

238

View full text Add to dashboard Cite

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“…At the same time, acting through the NAD + salvage pathway, it improves the metabolic state of hypoxic embryos, normalizes their production of ATP, and prevents FGR. Nicotinamide probably ameliorates the consequences of PE-associated ischemia in the same way that it protects the heart from ischemic reperfusion injury (25).…”

Section: Mechanisms Underlying the Effects Of Nicotinamide On Pregnancymentioning

confidence: 99%

Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia

Fushima

Oyanagi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Preeclampsia (PE) complicates ∼5% of human pregnancies and is one of the leading causes of pregnancy-related maternal deaths. The only definitive treatment, induced delivery, invariably results in prematurity, and in severe early-onset cases may lead to fetal death. Many currently available antihypertensive drugs are teratogenic and therefore precluded from use. Nonteratogenic antihypertensives help control maternal blood pressure in PE, but results in preventing preterm delivery and correcting fetal growth restriction (FGR) that also occurs in PE have been disappointing. Here we show that dietary nicotinamide, a nonteratogenic amide of vitamin B 3 , improves the maternal condition, prolongs pregnancies, and prevents FGR in two contrasting mouse models of PE. The first is caused by endotheliosis due to excess levels in the mothers of a soluble form of the receptor for vascular endothelial growth factor (VEGF), which binds to and inactivates VEGF. The second is caused by genetic absence of Ankiryn-repeat-and-SOCS-box-containingprotein 4, a factor that contributes to the differentiation of trophoblast stem cells into the giant trophoblast cells necessary for embryo implantation in mice; its absence leads to impaired placental development. In both models, fetal production of ATP is impaired and FGR is observed. We show here that nicotinamide decreases blood pressure and endotheliosis in the mothers, probably by inhibiting ADP ribosyl cyclase (ADPRC), and prevents FGR, probably by normalizing fetal ATP synthesis via the nucleotide salvage pathway. Because nicotinamide benefits both dams and pups, it merits evaluation for preventing or treating PE in humans.he maternal hypertension and proteinuria characterizing preeclampsia (PE) are primarily consequences of an imbalance between proangiogenic growth factors that promote vascular well-being (such as VEGF), and antiangiogenic factors that sequester the growth factors (such as the soluble form of VEGF receptor-1, now referred to as sFLT1) (1). Both the hypertension and the proteinuria of PE are caused by abnormally high amounts of antiangiogenic factors derived from the placenta. Fetal growth restriction (FGR), an additional feature of PE, is a consequence of reduced placental blood flow resulting from damage to the placental vasculature caused by antiangiogenic factors and/or to impaired development of the placenta. Endothelin-1 (EDN1) is the most powerful naturally occurring prohypertensive peptide, and antagonists of the endothelin type A receptor (EDNRA) greatly ameliorate the PE-like condition that develops in the kidneys of rodents with excess sFLT1 (2, 3). Unfortunately, these antagonists are teratogenic (4) and consequently unacceptable for use in treating PE.Nicotinamide is a potential nonteratogenic alternative because it relaxes blood vessels constricted with EDN1 (5) and because it has been extensively tested at high oral doses in men and (nonpregnant) women and found safe (6). Results and DiscussionNicotinamide Ameliorates the Hypertension, Albuminuria, an...

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“…5). In these models, NAD + precursor supplementation attenuates cardiomyopathy in mitochondrial complex I deficiency (6), extends lifespan in mice with cardiac iron deficiency from genetic ablation of transferrin receptor (7), protects against ischemia-reperfusion (I/R) injury induced ROS formation (8), and blunts development of chronic catecholamine-induced cardiac dysfunction (9). The molecular mechanisms underlying the cardio-protective effects of NAD + supplementation are poorly understood, which is an important conceptual barrier to translating NAD + precursor supplementation into clinical practice.…”

Section: Introductionmentioning

confidence: 99%