Nicotinamide phosphoribosyltransferase aggravates inflammation and promotes atherosclerosis in ApoE knockout mice

Kong, Yuanyuan; Li, Guoqiang; Zhang, Wenjie; Xia, Hua; Zhou, Cancan; Xu, Tao; Li, Zhiyong; Wang, Pei

doi:10.1038/s41401-018-0207-3

Cited by 27 publications

(17 citation statements)

References 56 publications

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“…It should be noted that cardiac-specific overexpression of Nampt also stimulated production of cytokines, including TNF-␣ and MCP-1, and activation of NF-B signaling at baseline and during PO. We and others have shown that Nampt itself can act as an inflammatory cytokine when overexpressed (14). Although myocardial infiltration of inflammatory cells was not significantly elevated in Tg-Nampt mice compared with in WT mice at baseline or in response to PO, it is possible that upregulation of proinflammatory mechanisms may contribute to the exacerbation of PO-induced cardiac dysfunction in Tg-Nampt mice.…”

Section: Discussionmentioning

confidence: 72%

Both gain and loss of Nampt function promote pressure overload-induced heart failure

Byun

Oka

Imai

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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The heart requires high-energy production, but metabolic ability declines in the failing heart. Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) synthesis. NAD is directly involved in various metabolic processes and may indirectly regulate metabolic gene expression through sirtuin 1 (Sirt1), an NAD-dependent protein deacetylase. However, how Nampt regulates cardiac function and metabolism in the failing heart is poorly understood. Here we show that pressure-overload (PO)-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout (Nampt+/−) mice and mice with cardiac-specific Nampt overexpression (Tg-Nampt). The NAD level declined in Nampt+/− mice under PO (wild: 377 pmol/mg tissue; Nampt+/−: 119 pmol/mg tissue; P = 0.028). In cultured cardiomyocytes, Nampt knockdown diminished mitochondrial NAD content and ATP production (relative ATP production: wild: 1; Nampt knockdown: 0.56; P = 0.0068), suggesting that downregulation of Nampt induces mitochondrial dysfunction. On the other hand, the NAD level was increased in Tg-Nampt mice at baseline but not during PO, possibly due to increased consumption of NAD by Sirt1. The expression of Sirt1 was increased in Tg-Nampt mice, in association with reduced overall protein acetylation. PO-induced downregulation of metabolic genes was exacerbated in Tg-Nampt mice. In cultured cardiomyocytes, Nampt and Sirt1 cooperatively suppressed mitochondrial proteins and ATP production, thereby promoting mitochondrial dysfunction. In addition, Nampt overexpression upregulated inflammatory cytokines, including TNF-α and monocyte chemoattractant protein-1. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, whereas Nampt overexpression is detrimental during PO, possibly due to excessive activation of Sirt1, suppression of mitochondrial function, and upregulation of proinflammatory mechanisms. NEW & NOTEWORTHY Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide synthesis. We demonstrate that pressure overload-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout mice and mice with cardiac-specific Nampt overexpression. Both loss- and gain-of-function models exhibited reduced protein acetylation, suppression of metabolic genes, and mitochondrial energetic dysfunction. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, but cardiac-specific Nampt overexpression is detrimental rather than therapeutic.

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Section: Discussionmentioning

confidence: 72%

Both gain and loss of Nampt function promote pressure overload-induced heart failure

Byun

Oka

Imai

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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“…The levels of NAMPT decrease with aging due to chronic inflammation, oxidative stress, and DNA damage [ 20 ]. In the cardiovascular system, NAMPT exacerbates atherosclerotic inflammation and promotes atherosclerosis development in ApoE mice [ 13 ]. NAMPT promotes pulmonary vascular remodeling, and its inhibition potentially represents a therapeutic strategy for pulmonary arterial hypertension (PAH) [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…NAMPT has been reported to be involved in various diseases and conditions, such as obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), cancer, and aging [ 11 ]. In the cardiovascular system, NAMPT promotes atherosclerosis development by exacerbating atherosclerotic inflammation [ 13 ]. NAMPT inhibits myocardial injury by regulating NAD and ATP levels [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

NAMPT/SIRT1 Attenuate Ang II-Induced Vascular Remodeling and Vulnerability to Hypertension by Inhibiting the ROS/MAPK Pathway

Zhou

Zhang

Bolor-Erdene

et al. 2020

Oxidative Medicine and Cellular Longevity

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Hypertension is characterized by endothelial dysfunction, vascular remodeling, and rearrangement of the extracellular matrix. Besides, the pathogenesis of hypertension is closely related to excess generation of reactive oxygen species (ROS). Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis that influences the activity of NAD-dependent enzymes, such as sirtuins, which possess NAD-dependent protein deacetylase activity and cleave NAD during the deacetylation cycle. Recently, NAMPT has been shown to play a crucial role in various diseases associated with oxidative stress. However, the function and regulation of NAMPT in hypertension have not been extensively explored. In the present study, we identified NAMPT as a crucial regulator of hypertension, because NAMPT expression was significantly downregulated in both patients with hypertension and experimental animals. NAMPT knockout (NAMPT+/-) mice exhibited a significantly higher blood pressure and ROS levels after stimulation with angiotensin II (Ang II) than wild-type mice, and the administration of recombinant human NAMPT (rhNAMPT) reversed this effect. In vivo, overexpression of NAMPT protected against angiotensin II- (Ang II-) induced hypertension by inhibiting ROS production via sirtuin 1 in mouse aortic endothelial cells (MAECs) and mouse aortic vascular smooth muscle cells (MOVAs). In turn, NAMPT alleviated the ROS-induced mitogen-activated protein kinase (MAPK) pathway. In conclusion, NAMPT might be a novel biomarker and a therapeutic target in hypertension.

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“…Nampt is involved in many important biological processes, including survival, apoptosis, metabolism and angiogenesis (16). As a cytokine, an elevated concentration of Nampt has been observed in several inflammatory and autoimmune disorders, such as sepsis, atherosclerosis, systemic lupus erythematosus and Crohn's disease (17)(18)(19)(20). Previous studies have demonstrated an elevated plasma Nampt concentration in Hashimoto's thyroiditis (HT) patients (14).…”

Section: Discussionmentioning

confidence: 99%

Role of Nampt overexpression in a rat model of Hashimoto's thyroiditis and its mechanism of action

Tang

Wei

et al. 2020

Exp Ther Med

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The present study was designed to investigate the role of nicotinamide phosphoribosyltransferase (Nampt) overexpression in a rat model of Hashimoto's thyroiditis (HT) and its mechanism of action. A rat model of HT was constructed, and the HT rats were injected with an adenoviral expression vector carrying the Nampt gene. The expression of Nampt and Toll-like receptor 4 (TLR4) in thyroid tissues was examined using immunohistochemistry (IHC), RT-qPCR and western blot analyses. Serum anti-thyroglobulin antibodies (TGAb) and anti-thyroid peroxidase antibodies (TPOAb) were measured using chemiluminescence method. Hematoxylin and eosin (H&E) and IHC staining of the rat thyroid tissues showed destroyed thyroid follicles and monocyte infiltration, as well as increased Nampt expression in the thyroid tissues of rats with HT. Furthermore, it was found that Nampt overexpression led to increased severity of inflammatory infiltration in thyroid tissues and increased levels of TPOAb in the serum of HT rats; however, the serum TGAb level was not affected by Nampt overexpression. In addition, Nampt overexpression promoted TLR4 expression in HT rats. In conclusion, it was demonstrated that Nampt was strongly expressed in the capillary region of HT rats thyroid tissues. The Nampt mRNA level was increased but the Nampt protein level was decreased in the thyroid tissues of rats with HT. Nampt overexpression has a promotive effect on HT progression, and this effect was related to TLR4. This study suggests that inhibition of Nampt activity may be valuable in the treatment of HT.

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Nicotinamide phosphoribosyltransferase aggravates inflammation and promotes atherosclerosis in ApoE knockout mice

Cited by 27 publications

References 56 publications

Both gain and loss of Nampt function promote pressure overload-induced heart failure

Both gain and loss of Nampt function promote pressure overload-induced heart failure

NAMPT/SIRT1 Attenuate Ang II-Induced Vascular Remodeling and Vulnerability to Hypertension by Inhibiting the ROS/MAPK Pathway

Role of Nampt overexpression in a rat model of Hashimoto's thyroiditis and its mechanism of action

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