Nicotinamide mononucleotide attenuates isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation

Wu, Keke; Li, Biao; Lin, Qiuzhen; Xu, Wanghan; Zuo, Wanyun; Li, Jiayi; Liu, Na; Tu, Tao; Zhang, Baojian; Xiao, Yichao; Liu, Qiming

doi:10.1016/j.lfs.2021.119299

Cited by 37 publications

(25 citation statements)

References 53 publications

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“…SIRT1, a lysine deacetylase, is a modulator of mitochondrial oxidative stress [ 3 ] and NOX4 expression [ 16 ]. It has been reported that its anti-fibrotic effect is associated with decreased mtROS [ 3 , 17 ]. It can also inhibit fibroblasts activation [ 3 , 17 ] and modulate lipid metabolism [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that its anti-fibrotic effect is associated with decreased mtROS [ 3 , 17 ]. It can also inhibit fibroblasts activation [ 3 , 17 ] and modulate lipid metabolism [ 19 ]. However, whether SIRT1 protect against LF activation by regulating mtNOX4- related mtROS and lipid metabolism and its mechanisms need to be further investigated.…”

Section: Introductionmentioning

confidence: 99%

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SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism

Zhang

Pan

et al. 2022

J Transl Med

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Background Cigarette smoking (CS) is a strong risk factor for idiopathic pulmonary fibrosis (IPF). It can activate lung fibroblasts (LF) by inducing redox imbalance. We previously showed that clearing mitochondrial reactive oxygen species (mtROS) protects against CS-induced pulmonary fibrosis. However, the precise mechanisms of mtROS in LF need further investigation. Here we focused on mtROS to elucidate how it was regulated by CS in LF and how it contributed to LF activation. Methods We treated cells with 1% cigarette smoking extract (CSE) and examined mtROS level by MitoSOX™ indicator. And the effect of CSE on expression of SIRT1, SOD2, mitochondrial NOX4 (mtNOX4), fatty acid oxidation (FAO)-related protein PPARα and CPT1a and LF activation marker Collagen I and α-SMA were detected. Nile Red staining was performed to show cellular lipid content. Then, lipid droplets, autophagosome and lysosome were marked by Bodipy 493/503, LC3 and LAMP1, respectively. And lipophagy was evaluated by the colocalization of lipid droplets with LC3 and LAMP1. The role of autophagy on lipid metabolism and LF activation were explored. Additionally, the effect of mitochondria-targeted ROS scavenger mitoquinone and SIRT1 activator SRT1720 on mitochondrial oxidative stress, autophagy flux, lipid metabolism and LF activation were investigated in vitro and in vivo. Results We found that CS promoted mtROS production by increasing mtNOX4 and decreasing SOD2. Next, we proved mtROS inhibited the expression of PPARα and CPT1a. It also reduced lipophagy and upregulated cellular lipid content, suggesting lipid metabolism was disturbed by CS. In addition, we showed both insufficient FAO and lipophagy resulted from blocked autophagy flux caused by mtROS. Moreover, we uncovered decreased SIRT1 was responsible for mitochondrial redox imbalance. Furthermore, we proved that both SRT1720 and mitoquinone counteracted the effect of CS on NOX4, SOD2, PPARα and CPT1a in vivo. Conclusions We demonstrated that CS decreased SIRT1 to activate LF through dysregulating lipid metabolism, which was due to increased mtROS and impaired autophagy flux. These events may serve as therapeutic targets for IPF patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism

Zhang

Pan

et al. 2022

J Transl Med

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“…However, to the best of our knowledge, this is the first report to evaluate the antioxidant effect of NMN in tendons. The antioxidant function of NMN has been linked to maintenance of mitochondrial homeostasis and increased levels of antioxidants [ 22 , 40 , 41 ]. Furthermore, SIRT1, which is stimulated by NMN, has been associated with suppressing oxidative stress by downregulating NOX production [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Antioxidant effect of nicotinamide mononucleotide in tendinopathy

Yamaura

Mifune

Inui

et al. 2022

BMC Musculoskelet Disord

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Background A link between tendinopathy and oxidative stress has been recently reported. Nicotinamide mononucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide, which plays an important role in cell redox homeostasis. The aim of this study was to evaluate the antioxidant effect of NMN on tendinopathy in vitro and in vivo. Methods Tenocytes from healthy Sprague-Dawley rats were cultured in regular glucose (RG) and high-glucose (HG) conditions with or without NMN, and were divided into four groups: RG NMN(−), RG NMN(+), HG NMN(−), and HG NMN(+). Cell viability, reactive oxygen species (ROS) accumulation, apoptotic rate, and mRNA expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX)1, NOX4, interleukin (IL)6, sirtuin (SIRT)1, and SIRT6 were investigated. In addition, rats with collagenase-induced tendinopathy were treated with or without NMN. Immunostaining of NOX1 and NOX4; mRNA expression of SIRT1, SIRT6, and IL6; and superoxide dismutase (SOD) activity measurements in the Achilles tendon were performed. Results NMN increased the expression of SIRT1 and SIRT6 in rat tenocytes, but decreased the levels of NOX1, NOX4, IL6, ROS, and apoptosis. In Achilles tendons with collagenase-induced tendinopathy, NMN increased the mRNA expression of SIRT1 and SIRT6, as well as SOD activity; while suppressing protein expression of NOX1 and NOX4, and mRNA expression of IL6. Conclusion The in vitro and in vivo results of this study show that NMN exerts an antioxidant effect on tendinopathy by promoting the expression of SIRT while inhibiting that of NOX.

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“…Such deacetylation of transcription factors related to metabolism could lead to intracellular changes. It has been reported that Sirt1 attenuates hepatic (Zhao et al, 2018), cardiac (Wu et al, 2021), renal (Liu et al, 2020), and pulmonary (Mazumder et al, 2020;Peterson et al, 1986) IL-11 and IL-11Rα1 are expressed specifically in fibroblasts, in which they drive noncanonical, ERK-dependent autocrine signaling that is required for fibrogenic protein synthesis (Schafer et al, 2017). Fibroblasts derived from the mesenchyme play a regulatory role in several organs.…”

Section: Sirt1 Negatively Regulates Il-11 Expression By Deacetylating...mentioning

confidence: 99%

Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription

et al. 2022

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Determining the mechanism of senescence‐associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence‐associated pulmonary fibrosis by activating TGF‐β1/IL‐11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF‐β1/IL‐11/MEK/ERK signaling‐mediated senescence‐associated pulmonary fibrosis in vitamin D‐deficient (Cyp27b1−/−) mice, and whether Sirt1 downregulated IL‐11 expression transcribed by TGF‐β1/Smad2 signaling through deacetylating histone at the IL‐11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild‐type (WT) mice were examined for cell senescence, fibrosis markers, and TGF‐β1/IL‐11/MEK/ERK signaling proteins, and 1,25(OH)2D3 and IL‐11 levels were detected in serum. Nine‐week‐old WT, Sirt1 mesenchymal transgene (Sirt1Tg), Cyp27b1−/−, and Sirt1TgCyp27b1−/− mice were observed the pulmonary function, aging, and senescence‐associated secretory phenotype and TGF‐β1/IL‐11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF‐β1/IL‐11/MEK/ERK signaling, and promoting senescence‐associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence‐associated secretory phenotype, and fibrosis through downregulating TGF‐β1/IL‐11/MEK/ERK signaling in Cyp27b1−/− mice. Sirt1 negatively regulated IL‐11 expression through deacetylating H3K9/14ac mainly at the region from −871 to −724 of IL‐11 promoter, also the major binding region of Smad2 which regulated IL‐11 expression at the transcriptional level, and subsequently inhibiting TGF‐β1/IL‐11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence‐associated pulmonary fibrosis induced by vitamin D deficiency.

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Nicotinamide mononucleotide attenuates isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation

Cited by 37 publications

References 53 publications

SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism

SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism

Antioxidant effect of nicotinamide mononucleotide in tendinopathy

Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription

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