Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism

Sun, Dan; Yang, Fei

doi:10.1016/j.bbrc.2017.03.036

Cited by 60 publications

(51 citation statements)

References 29 publications

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“…The effect on angiogenesis in one of these studies and in and in other experimental studies was associated with stimulation of the AMPK/inhibition of mTOR by metformin, which suggests that such a mechanism may be of relevance to the clinical therapeutic action of metformin. Other potentially vascular protective mechanisms described for metformin in experimental studies include reduced cholesterol uptake or enhanced cholesterol efflux from macrophages, inhibition of fission of mitochondria in endothelial cells, protection of mitochondrial function during and after myocardial ischaemia, and reduced formation of foam cells or neointima in the developing plaque.…”

Section: Cardiovascular Protection With Metforminmentioning

confidence: 99%

Mechanisms of action of metformin with special reference to cardiovascular protection

Zilov

Abdelaziz

Alshammary

et al. 2019

Diabetes Metabolism Res

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Summary Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin‐stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP‐1 from intestinal L‐cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin‐treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin‐based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.

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Section: Cardiovascular Protection With Metforminmentioning

confidence: 99%

Mechanisms of action of metformin with special reference to cardiovascular protection

Zilov

Abdelaziz

Alshammary

et al. 2019

Diabetes Metabolism Res

View full text Add to dashboard Cite

show abstract

“…Recently, inducers of autophagy, such as rapamycin, metformin, and resveratrol, have shown cardioprotective effects after MI (Kanamori et al, ; Filippone et al, ; D. Sun & Yang, ). Spermidine also promotes health by induction of autophagy (Madeo, Eisenberg, Pietrocola, & Kroemer, ).…”

Section: Introductionmentioning

confidence: 99%

Spermidine‐enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway

Yan

Wang

Ling

et al. 2019

British J Pharmacology

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Background and Purpose Spermidine, a natural polyamine, is abundant in mammalian cells and is involved in cell growth, proliferation, and regeneration. Recently, oral spermidine supplements were cardioprotective in age‐related cardiac dysfunction, through enhancing autophagic flux. However, the effect of spermidine on myocardial injury and cardiac dysfunction following myocardial infarction (MI) remains unknown. Experimental Approach We determined the effects of spermidine in a model of MI, Sprague–Dawley rats with permanent ligation of the left anterior descending artery, and in cultured neonatal rat cardiomyocytes (NRCs) exposed to angiotensin II (Ang II). Cardiac function in vivo was assessed with echocardiography. In vivo and in vitro studies used histological and immunohistochemical techniques, along with western blots. Key Results Spermidine improved cardiomyocyte viability and decreased cell necrosis in NRCs treated with angiotensin II. In rats post‐MI, spermidine reduced infarct size, improved cardiac function, and attenuated myocardial hypertrophy. Spermidine also suppressed the oxidative damage and inflammatory cytokines induced by MI. Moreover, spermidine enhanced autophagic flux and decreased apoptosis both in vitro and in vivo. The protective effects of spermidine on cardiomyocyte apoptosis and cardiac dysfunction were abolished by the autophagy inhibitor chloroquine, indicating that spermidine exerted cardioprotective effects at least partly through promoting autophagic flux, by activating the AMPK/mTOR signalling pathway. Conclusions and Implications Our findings suggest that spermidine improved MI‐induced cardiac dysfunction by promoting AMPK/mTOR‐mediated autophagic flux.

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“…While a causal relationship between Vinculin and OCR has not been previously established to our knowledge, these data are consistent with improved cardiac function resulting from pharmacologically mediated improvements in mitochondrial respiration. 28 …”

Section: Resultsmentioning

confidence: 99%

Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span

et al. 2018

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Despite limited regenerative capacity as we age, cardiomyocytes maintain their function in part through compensatory mechanisms, e.g., Vinculin reinforcement of intercalated discs in aged organisms. This mechanism, which is conserved from flies to non-human primates, creates a more crystalline sarcomere lattice that extends lifespan, but systemic connections between the cardiac sarcomere structure and lifespan extension are not apparent. Using the rapidly aging fly system, we found that cardiac-specific Vinculin-overexpression [Vinculin heart-enhanced (VincHE)] increases heart contractility, maximal cardiac mitochondrial respiration, and organismal fitness with age. Systemic metabolism also dramatically changed with age and VincHE; steady state sugar concentrations, as well as aerobic glucose metabolism, increase in VincHE and suggest enhanced energy substrate utilization with increased cardiac performance. When cardiac stress was induced with the complex I inhibitor rotenone, VincHE hearts sustain contractions unlike controls. This work establishes a new link between the cardiac cytoskeleton and systemic glucose utilization and protects mitochondrial function from external stress.

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Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism

Cited by 60 publications

References 29 publications

Mechanisms of action of metformin with special reference to cardiovascular protection

Mechanisms of action of metformin with special reference to cardiovascular protection

Spermidine‐enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway

Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span

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