Cardioprotective Effects of SIRT6 in a Mouse Model of Transverse Aortic Constriction-Induced Heart Failure

Li, Yongming; Meng, Xianda; Wang, Wenguang; Fu, Liu; Zeng, Hao; Yang, Yang; Zhao, Jinbo; Yin, Weidong; Xu, Lijuan; Zhao, Ruiping; Hu, Jiang

doi:10.3389/fphys.2017.00394

Cited by 37 publications

(24 citation statements)

References 35 publications

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“…24 As an important member of sirtuin family, SIRT6 is mainly located in the nucleus and its activation exerts protective effects against myocardial infarction, 25 cardiac hypertrophy, 26 and heart failure. 27 Besides, numerous studies have reported that sirtuins mediated the pleiotropic actions of melatonin in various disease models. 24 However, to the best of our knowledge, there are few studies investigating the role of SIRT6 in the modulatory actions of melatonin in pathological condition.…”

Section: Introductionmentioning

confidence: 99%

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

Dong

Xue

et al. 2020

Journal of Pineal Research

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156

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Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high‐fat diet‐streptozotocin‐induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK‐PGC‐1α‐AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia‐reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re‐activating SIRT6 and AMPK‐PGC‐1α‐AKT signaling. After the induction of diabetes, adeno‐associated virus carrying SIRT6‐specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin‐induced AMPK‐PGC‐1α‐AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long‐term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor‐mediated SIRT6‐AMPK‐PGC‐1α‐AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia‐reperfusion injury in diabetic patients.

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Section: Introductionmentioning

confidence: 99%

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

Dong

Xue

et al. 2020

Journal of Pineal Research

Self Cite

156

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“…In this study, we found that SIRT6 knockdown in oocytes causes the reduction in telomere length in early embryos. Telomere-binding proteins TRF1 and TRF2 bind specifically to the double-stranded TTAGGG repeats, and are important for the control of telomeric length and structure [33]. TRF1 has been reported to play a key role in both telomerase-dependent telomere maintenance and alternative lengthening [34, 35].…”

Section: Discussionmentioning

confidence: 99%

SIRT6 participates in the quality control of aged oocytes via modulating telomere function

et al. 2019

Aging

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It has been well recognized that oocyte quality declines in aging animals. However, to date, the underlying mechanism remains to be explored. In the present study, we report that oocytes and embryos from aged mice (42-45 weeks old) display the reduced expression of SIRT6 protein, accompanying with telomere shortening and DNA lesions. Moreover, we demonstrate that specific depletion of SIRT6 in oocytes induces dysfunctional telomeres and apoptosis of the resultant early embryos, leading to the developmental delay and cytoplasmic fragmentation. Importantly, we further find that overexpression of SIRT6 in aged oocytes promotes the telomere elongation in 2-cell embryos and lowers the incidence of apoptotic blastomeres. In summary, our data indicate a role for SIRT6 in modulating telomere function during oocyte maturation and embryonic development, and discover that SIRT6 reduction is an important point connecting maternal aging and quality control of oocyte/embryos.

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“…damage, Gao et al (41) observed that SIRT6 was required for directional telomere movement, a process that facilitates efficient DNA damage repair at telomeric chromatin. Additionally, SIRT6 overexpression in mice was reported to up-regulate telomerase reverse transcriptase and telomere repeat binding factor, although this study did not explore the mechanism of upregulation or potential downstream effects on telomere length (42). Proper mitosis requires condensed and silenced pericentric heterochromatin at centromeres to protect against genomic instability and cellular senescence during cell division.…”

Section: Dna Repair and Chromatin Maintenancementioning

confidence: 95%

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

Klein

Denu

2020

Journal of Biological Chemistry

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Sirtuin 6 (SIRT6) is a nuclear NAD+-dependent deacetylase of histone H3 that regulates genome stability and gene expression. However, non-histone substrates and additional catalytic activities of SIRT6, including long-chain deacylation and mono-ADP-ribosylation of other proteins have also been reported, but many of these non-canonical roles remain enigmatic. Genetic studies have revealed critical homeostatic cellular functions of SIRT6, underscoring the need to better understand which catalytic functions and molecular pathways are driving SIRT6-associated phenotypes. At the physiological level, SIRT6 activity promotes increased longevity by regulating metabolism andDNA repair. Recent work has identified natural products and synthetic small-molecules capable of activating the inefficient in vitrodeacetylase activity of SIRT6. Here, we discuss the cellular functions of SIRT6 with a focus on attributing its catalytic activity to its proposed biological functions. We cover the molecular architecture and catalytic mechanisms that distinguish SIRT6 from other NAD+-dependent deacylases. We propose that combining specific SIRT6 amino-acid substitutions identified in enzymology studies, and activity-selective compounds could help delineate SIRT6 functions in specific biological contexts and resolve the apparently conflicting roles of SIRT6 in processes such as tumor development. We further highlight the recent development of small-molecule modulators that provide additional biologicalinsight into SIRT6 functions and offer therapeutic approaches to manage metabolic and age-associated diseases.

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Cardioprotective Effects of SIRT6 in a Mouse Model of Transverse Aortic Constriction-Induced Heart Failure

Cited by 37 publications

References 35 publications

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

SIRT6 participates in the quality control of aged oocytes via modulating telomere function

Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators

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