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

ABSTRACT: 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.

SUBMITTER: Zhou L

PROVIDER: S-EPMC7791967 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Zhou Lei L Zhang Sheng S Bolor-Erdene Enkhbat E Wang Lingwei L Tian Ding D Mei Yunqing Y

Oxidative medicine and cellular longevity 20201230

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 ...[more]

PMID: 33488923

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Project description:Glyoxalase I (GLO1) is the primary enzyme for detoxification of the reactive dicarbonyl methylglyoxal (MG). Loss of GLO1 promotes accumulation of MG resulting in a recapitulation of diabetic phenotypes. We previously demonstrated attenuated GLO1 protein in skeletal muscle from individuals with type 2 diabetes (T2D). However, whether GLO1 attenuation occurs prior to T2D and the mechanisms regulating GLO1 abundance in skeletal muscle are unknown. GLO1 expression and activity were determined in skeletal muscle tissue biopsies from 15 lean healthy individuals (LH, BMI: 22.4 ± 0.7) and 5 individuals with obesity (OB, BMI: 32.4 ± 1.3). GLO1 protein was attenuated by 26 ± 0.3 % in OB compared to LH skeletal muscle (p = 0.019). Similar reductions for GLO1 activity were observed (p = 0.102). NRF2 and Keap1 expression were equivocal between groups despite a 2-fold elevation in GLO1 transcripts in OB skeletal muscle (p = 0.008). GLO1 knock-down (KD) in human immortalized myotubes promoted downregulation of muscle contraction and organization proteins indicating the importance of GLO1 expression for skeletal muscle function. SIRT1 KD had no effect on GLO1 protein or activity whereas, SIRT2 KD attenuated GLO1 protein by 28 ± 0.29 % (p < 0.0001) and GLO1 activity by 42 ± 0.12 % (p = 0.0150). KD of NAMPT also resulted in attenuation of GLO1 protein (28 ± 0.069 %, p = 0.003), activity (67 ± 0.09 %, p = 0.011) and transcripts (50 ± 0.13 %, p = 0.049). Neither the provision of the NAD+ precursors NR nor NMN were able to prevent this attenuation in GLO1 protein. However, NR did augment GLO1 specific activity (p = 0.022 vs NAMPT KD). These perturbations did not alter GLO1 acetylation status. SIRT1, SIRT2 and NAMPT protein levels were all equivocal in skeletal muscle tissue biopsies from individuals with obesity and lean individuals. These data implicate NAD+-dependent regulation of GLO1 in skeletal muscle independent of altered GLO1 acetylation and provide rationale for exploring NR supplementation to rescue attenuated GLO1 abundance and activity in conditions such as obesity.

Project description:We previously demonstrated involvement of NAMPT (nicotinamide phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now examine NAMPT regulation and extracellular NAMPT's (eNAMPT's) role in PAH vascular remodeling. NAMPT transcription and protein expression in human lung endothelial cells were assessed in response to PAH-relevant stimuli (PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor], TGF-β1 [transforming growth factor-β1], and hypoxia). Endothelial-to-mesenchymal transition was detected by SNAI1 (snail family transcriptional repressor 1) and PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly increased in patients with idiopathic pulmonary arterial hypertension, were highly correlated with indices of PAH severity. eNAMPT increased endothelial-to-mesenchymal transition, and each PAH stimulus significantly increased endothelial cell NAMPT promoter activity involving transcription factors STAT5 (signal transducer and activator of transcription 5), SOX18 (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a PAH candidate gene newly defined by genome-wide association study. The hypoxia-induced transcription factor HIF-2α (hypoxia-inducible factor-2α) also potently regulated NAMPT promoter activity, and HIF-2α binding sites were identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase domain-containing protein 2) inhibitor FG-4592 significantly increased NAMPT promoter activity and protein expression in an HIF-2α-dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling.

Dataset Information

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

Publications

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

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