Metformin promotes autophagy in ischemia/reperfusion myocardium via cytoplasmic AMPKα1 and nuclear AMPKα2 pathways

Wang, Yishi; Yang, Zuozhang; Zheng, Guoxu; Yu, Lu; Yin, Yulong; Ma, Nan; Ma, Heng

doi:10.1016/j.lfs.2019.04.002

Cited by 56 publications

(34 citation statements)

References 33 publications

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“…It is noteworthy that metformin also stimulates autophagy, primarily by activating AMPK and SIRT1 . These actions may contribute to the cardioprotective effects of the drug seen in experimental models of hypertrophy and heart failure, and they are consistent with favourable effects of metformin on the clinical course of heart failure that have been observed in non‐randomized cohort studies .…”

Section: Novel Mechanisms By Which Sglt2 Inhibitors May Promote Cardisupporting

confidence: 70%

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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Section: Novel Mechanisms By Which Sglt2 Inhibitors May Promote Cardisupporting

confidence: 70%

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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“…ese shreds of evidence show that AMPK activation is important not only in autophagosome formation but also in autophagosome clearance and can improve the overall autophagic clearance of aberrant proteins. is was corroborated with many other pharmacological studies in which the role of AMPK in autophagic flux is demonstrated [63,70,71]. For instance, Chen et al showed that AMPK activation with metformin enhances the autophagosomes clearance.…”

Section: Ampk and Aβ Metabolismsupporting

confidence: 65%

“…For instance, Chen et al showed that AMPK activation with metformin enhances the autophagosomes clearance. ey showed that AMPK-induced overall autophagy is inhibited by chloroquine, an autophagy inhibitor which works by inhibiting lysosomal acidification and degradation [71].…”

Section: Ampk and Aβ Metabolismmentioning

confidence: 99%

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

Assefa

Tafere

Wondafrash

et al. 2020

BioMed Research International

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Alzheimer’s disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.

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“…Metformin has been show to activate AMPK in adipose tissue [102], skeletal muscle [103] and hepatocytes, which decreases the activity of acetyl-CoA carboxylase, thereby reducing fatty acid synthesis and improving fatty acid oxidation [104]. In the heart, metformin promotes autophagy by both cytoplasmic AMPKα1 and nuclear AMPKα2 pathways [105], while it attenuates cardiac fibrosis through the TGFβ-SMAD3 pathway independent of AMPK [106].…”

Section: Metforminmentioning

confidence: 99%

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

Timm

Tyler

2020

Cardiovasc Drugs Ther

129

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Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate-activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.

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Metformin promotes autophagy in ischemia/reperfusion myocardium via cytoplasmic AMPKα1 and nuclear AMPKα2 pathways

Cited by 56 publications

References 33 publications

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

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

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

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