SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy

Lu, Jing; Sun, Duanping; Liu, Zhiping; Li, Min; Hong, HuiQi; Liu, Cui; Gao, Si; Li, Hong; Cai, Yi; Chen, Shao‐Rui; Li, Zhuoming; Ye, Jiantao

doi:10.1016/j.trsl.2016.03.002

Cited by 79 publications

(70 citation statements)

References 62 publications

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“…SIRT6 was reported to be crucial in protecting the aorta from maldevelopment and AS ; however, its involvement in macrophage function and the underlying mechanisms have not been studied yet. Given that SIRT6 is involved in modulating autophagy in several cell types , it is consistent that it also regulates autophagy in macrophages. Interestingly, our data showed that SIRT6 induced autophagy flux more evidently after ox‐LDL treatment.…”

Section: Discussionmentioning

confidence: 84%

“…In neuronal models, SIRT6 was reported to aggravate oxidative stress induced by neural damage through an increase in autophagy and ROS production [29]. Additionally, autophagy induction by SIRT6 has been associated also with protecting cardiomyocytes from hypertrophy caused by isoproterenol treatment [30]. However, the connection between SIRT6 and autophagy in macrophages and its impact on the pathological development of AS have not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

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SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox‐LDL condition

et al. 2017

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SIRT6 is a pivotal regulator of lipid metabolism. It is also closely connected to cardiovascular diseases, which are the main cause of death in diabetic patients. We observed a decrease in the expression of SIRT6 and key autophagy effectors (ATG5, LC3B, and LAMP1) in ox-LDL-induced foam cells, a special form of lipid-laden macrophages. In these cells, SIRT6 WT but not SIRT6 H133Y overexpression markedly reduced foam cell formation, as shown by Oil Red O staining, while inducing autophagy flux, as determined by both mRFP-GFP-LC3 labeling and transmission electron microscopy. Silencing the key autophagy initiation gene ATG5, reversed the autophagy-promoting effect of SIRT6 in ox-LDL-treated THP1 cells, as evidenced by an increase in foam cells. Cholesterol efflux assays indicated that SIRT6 overexpression in foam cells promoted cholesterol efflux, increased the levels of ABCA1 and ABCG1, and reduced miR-33 levels. By transfecting miR-33 into cells overexpressing SIRT6, we observed that reduced foam cell formation and autophagy flux induction were largely reversed. These data imply that SIRT6 plays an essential role in protecting against atherosclerosis by reducing foam cell formation through an autophagy-dependent pathway.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox‐LDL condition

et al. 2017

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“…Interestingly, several studies have demonstrated that SIRT6 functions as a positive regulator of autophagy in some cell types, such as bronchial epithelial cells, cardiomyocytes and neurons. In these cells, SIRT6 regulates the autophagy process via inhibiting the AKT activity (Lu, et al 2016; Shao, et al 2016; Takasaka, et al 2014). Considering a critical role of autophagy in PA-induced β-cell dysfunction, it is reasonable to postulate that SIRT6 may exert a protective effect against the PA-induced β-cell dysfunction and apoptosis through modulation of autophagy.…”

Section: Discussionmentioning

confidence: 99%

SIRT6 protects against palmitate-induced pancreatic β-cell dysfunction and apoptosis

Xiong

Sun

Wang

et al. 2016

Journal of Endocrinology

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Chronic exposure of pancreatic β-cells to abnormally elevated levels of free fatty acids can lead to β-cell dysfunction and even apoptosis, contributing to type 2 diabetes pathogenesis. In pancreatic β-cells, SIRT6 has been shown to regulate insulin secretion in response to glucose stimulation. However, what roles SIRT6 play in β-cells in response to lipotoxicity remain poorly understood. Our data indicated that SIRT6 protein and mRNA levels were reduced in islets from diabetic and aged mice. High concentrations of palmitate also led to a decrease in SIRT6 expression in MIN6 β-cells and resulted in cell dysfunction and apoptosis. Knockdown of Sirt6 caused an increase in cell apoptosis and impairment in insulin secretion in response to glucose in MIN6 cells even in the absence of high palmitate. Furthermore, overexpression of SIRT6 alleviated the palmitate-induced lipotoxicity with improved cell viability and increased glucose-stimulated insulin secretion. In summary, our data suggest that SIRT6 can protect against palmitate-induced β-cell dysfunction and apoptosis.

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“…As described previously, 38 the rats were anesthetized with 10% chloral hydrate (0.35 mg/kg) and were connected to a ventilator through endotracheal intubation. As described previously, 38 the rats were anesthetized with 10% chloral hydrate (0.35 mg/kg) and were connected to a ventilator through endotracheal intubation.…”

Section: Intramyocardial Delivery Of Recombinant Adenovirus Of Parp1mentioning

confidence: 99%

Poly(ADP‐ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity

Sun

Zheng

et al. 2019

J of Cellular Biochemistry

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Cardiac fibrosis is involved in nearly all forms of heart diseases, and is characterized by excessive deposition of extracellular matrix (ECM) proteins by cardiac fibroblasts (CFs). We and others have reported the possibility of poly(ADP-ribose) polymerase 1 (PARP1), the founding subtype of the PARPs enzyme family, as a novel therapeutic target of heart diseases. The cardiac fibrotic induction of mTOR (mammalian target of rapamycin) is mainly due to collagen expression, Smad3 and p53/JNK-mediated apoptosis. However, the possible link between PARP1 and mTOR in the progression of cardiac fibrosis remains unclear. In this study, PARP1 protein expression, and the activity of mTOR and its three target substrates (S6K1, 4E-BP and ULK1) were augmented; meanwhile, the NAD content was significantly reduced in the process of cardiac fibrosis in vivo and in vitro. SD rats were intraperitoneally injected with 3AB (20 mg/kg/d, a well-established PARP1 inhibitor) or rapamycin (Rapa, 1 mg/kg/d, used for mTOR inhibition) 7 days after AAC (abdominal aortic constriction) surgery for 6 weeks. Pre-treatment of 3AB or Rapa both relieved AAC-caused cardiac fibrosis and heart dysfunction. Overexpression of PARP1 with adenovirus carrying PARP1 gene (Ad-PARP1) specifically transduced into the hearts via intramyocardial multi-point injection caused similar myocardial damage. In CFs, pre-incubation with PARP1 or mTOR inhibitors all blocked TGF-β1-induced cardiac fibrosis. PARP1 overexpression evoked cardiac fibrosis, which could be antagonized by mTOR inhibitors or NAD supplementation in CFs. These results provide novel and compelling evidence that PARP1 exacerbated cardiac fibrosis, which was partially attributed to NAD-dependent activation of mTOR. This article is protected by copyright. All rights reserved.

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SIRT6 suppresses isoproterenol-induced cardiac hypertrophy through activation of autophagy

Cited by 79 publications

References 62 publications

SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox‐LDL condition

SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox‐LDL condition

SIRT6 protects against palmitate-induced pancreatic β-cell dysfunction and apoptosis

Poly(ADP‐ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity

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