Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury

Wang, Lin; Quan, Nanhu; Sun, Wanqing; Chen, Xu; Cates, Courtney; Rousselle, Thomas; Zhou, Xinchun; Zhao, Xiaohui; Li, Ji

doi:10.1093/cvr/cvy033

Cited by 105 publications

(92 citation statements)

References 68 publications

(94 reference statements)

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“…AMPK, which acts as a conserved energy sensor, is the target of SIRT1 for regulation of cellular metabolism. Briefly, SIRT1 deacetylates LKB1, and then LKB1 is translocated from the nucleus to the cytoplasm, forms an active complex and activates AMPKα 25,33 . As metabolic sensors, SIRT1/AMPK signaling was shown to play important role in metabolism 33 .…”

Section: Discussionmentioning

confidence: 99%

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

Wang

et al. 2020

Cell Death Dis

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Chemotherapy is the standard care for patients with gastric cancer (GC); however, resistance to existing drugs has limited its success. The persistence of cancer stem cells (CSCs) is considered to be responsible for treatment failure. In this study, we demonstrated that SIRT1 expression was significantly downregulated in GC tissues, and that a low SIRT1 expression level indicated a poor prognosis in GC patients. We observed a suppressive role of SIRT1 in chemoresistance of GC both in vitro and in vivo. In addition, we found that SIRT1 eliminated CSC properties of GC cells. Mechanistically, SIRT1 exerted inhibitory activities on chemoresistance and CSC properties through FOXO3 and AMPK. Furthermore, a synergistic effect was revealed between FOXO3 and AMPK. AMPK promoted nuclear translocation of FOXO3 and enhanced its transcriptional activities. In addition, FOXO3 increased the expression level and activation of AMPKα by directly binding to its promoter and activating the transcription of AMPKα. Similar to SIRT1, low expression levels of p-AMPKα and FOXO3a are also related to the poor prognosis of GC patients. Moreover, we revealed a correlation between the expression levels of SIRT1, p-AMPKα, and FOXO3a. These findings indicated the importance of the SIRT1-AMPK/FOXO3 pathway in reversing chemoresistance and CSC properties of GC. Thus, exploring efficient strategies to activate the SIRT1-AMPK/FOXO3 pathway may lead to improving the survival of GC patients.

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Section: Discussionmentioning

confidence: 99%

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

Wang

et al. 2020

Cell Death Dis

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“…Dr Li's study clearly showed that the impaired AMPK activation in aged hearts was at least in part due to decreased SIRT1 activity. 4 Increased expression of SIRT1 via adenoviral transfection rescued the attenuation of AMPK activation and reduced ischaemic injury, providing key mechanistic support. Interestingly, they also found that there was a feedback interaction between AMPK and SIRT1 activation.…”

mentioning

confidence: 89%

“…3 Dr Li et al found that the substrate flexibility was markedly impaired in aged hearts following IR compared with young hearts. 4 They further found that the decreased substrate flexibility was due in part to impairment of the AMPK (AMP-activated protein kinase) signalling pathway activation. Glucose uptake and utilization was decreased in parallel with enhanced fatty acid oxidation.…”

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confidence: 99%

“…Glucose uptake and utilization was decreased in parallel with enhanced fatty acid oxidation. 4 AMPK contributes an essential role in the regulation of glucose and lipid metabolism. Activation of the AMPK leads to increased glucose uptake and enhances insulin sensitivity.…”

mentioning

confidence: 99%

“…Mitochondrial DNA (mtDNA) was further damaged in aged hearts by IR. 4 Cytochrome b, a key catalytic subunit of Complex III, is encoded by mtDNA. Age-related defects in Cytochrome b lead to decreased Complex III activity in aged hearts.…”

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confidence: 99%

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A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1

Chen

Lesnefsky

2018

Cardiovascular Research

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This editorial refers to 'Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury' by L. Wang et al., Myocardial injury is increased in aged hearts during ischaemia-reperfusion (IR) and accelerates the transition to post-infarct heart failure. 1Although many therapeutic interventions can effectively decrease cardiac injury in younger adult hearts, strategies to decrease cardiac injury in aged hearts are still limited.1 Therefore, understanding the mechanisms of injury in the aged heart during IR is critical to develop potential strategies to protect the high-risk aged heart. 2The impairment of substrate flexibility (balance between glucose usage and fatty acid oxidation) contributes to cardiac injury during IR as well as heart failure development.3 Limitation of glucose utilization and oxidation with concomitant increased fatty acid oxidation during reperfusion enhances cardiac injury. 3 Dr Li et al. found that the substrate flexibility was markedly impaired in aged hearts following IR compared with young hearts. 4 They further found that the decreased substrate flexibility was due in part to impairment of the AMPK (AMP-activated protein kinase) signalling pathway activation. Glucose uptake and utilization was decreased in parallel with enhanced fatty acid oxidation. 4 AMPK contributes an essential role in the regulation of glucose and lipid metabolism. Activation of the AMPK leads to increased glucose uptake and enhances insulin sensitivity. 5 Liver kinase B1 (LKB1) is an AMP-activated kinase that activates AMPK through phosphorylation of the alpha subunit of AMPK. 6The activity of LKB1 is regulated by SIRT1 (sirtuin 1), a member of the sirtuin (NAD-dependent deacetylase) family. 7 Activation of SIRT1 leads to deacetylation and activation of LKB1 that increases AMPK phosphorylation and activity. Thus, SIRT1-dependent activation of LKB1 stimulates AMPK activity. Dr Li's study clearly showed that the impaired AMPK activation in aged hearts was at least in part due to decreased SIRT1 activity.

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Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Packer

2020

European J of Heart Fail

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In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1 /2 . The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1 /2 to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.In four large-scale clinical trials in patients with type 2 diabetes followed for 2-5 years who largely did not have a diagnosis of heart failure at the time of study entry, patients assigned to treatment

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Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury

Abstract: Cardiac SIRT1 mediates AMPK activation via LKB1 deacetylation, and AMPK modulates SIRT1 activity via regulation of NAD+ level during ischaemia. SIRT1 and AMPK agonists have therapeutic potential for treatment of aging-related ischemic heart disease.

Cited by 105 publications

References 68 publications

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

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