Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening

Bhamra, Gurpreet S.; Hausenloy, Derek J.; Davidson, Sean M.; Carr, Richard D.; Paiva, Marta; Wynne, Abigail; Mocanu, Mihaela M.; Yellon, Derek M.

doi:10.1007/s00395-007-0691-y

Cited by 185 publications

(141 citation statements)

References 54 publications

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“…These data clearly demonstrate the functional importance of GPER during the early phase of reperfusion. Our findings are consistent with those of previous studies demonstrating that mediators of myocardial protection target the start of reperfusion in order to limit cell death via reducing necrosis and apoptosis (31,32).…”

Section: Discussionsupporting

confidence: 83%

G-protein coupled estrogen receptor 1 expression in rat and human heart: Protective role during ischaemic stress

Patel

Chen²,

Ramanjaneya³

et al. 2010

Int J Mol Med

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Abstract. G-protein coupled estrogen receptor 1, GPER, formerly known as GPR30, is a seven transmembrane domain receptor that mediates rapid estrogen responses in a wide variety of cell types. To date, little is known about the role of GPER during ischaemia/reperfusion injury. In this study, we report both mRNA and protein expression of GPER in the rat and human heart. The role of GPER in estrogen protection against ischaemic stress in the rat heart was also assessed using the isolated Langendorff system. Pre-treatment with 17ß-estradiol (E2) significantly decreased infarct size, (61.48±2.2% to 27.92±2.9% (P<0.001). Similarly, treatment with the GPER agonist G1 prior to 30-min global ischaemia followed by 120-min reperfusion significantly reduced infarct size from 61.48±2.2% to 23.85±3.2% (P<0.001), whilst addition of GPR30 antibody, abolished the protective effect of G1 (infarct size: 55.42±1.3%). The results suggest that GPER under cardiac stress exerts direct protection in the heart and may serve as a potential therapeutic target for cardiac drug therapy. IntroductionEstrogens play critical regulatory roles in the physiology and development of numerous organs through binding to specific receptors (1). The female reproductive system, including the uterus and the breast, are major targets of estrogen actions. In addition, estrogens act on non-reproductive organs such as the brain, liver, and heart. Epidemiological studies have documented a lower incidence of coronary heart disease in premenopausal women compared with age-matched postmenopausal women and compared with men, suggesting a protective role of estrogens at the cardiac level (2,3). This cardioprotective effect has been further corroborated in rodent models (4-8). Two isoforms of nuclear estrogen receptors termed ER· and ERß mediate genomic responses to estrogens, and have distinct, non-overlapping physiological functions. Upon activation, the ligand-activated nuclear estrogen receptor dimerises and can directly interact with estrogen response elements in the promoter region of target genes, leading to activation/repression of gene transcription (9-12).Over the past 20 years many research groups have shown that steroids also act at the cell surface of many target tissues and cell types to initiate rapid responses, via binding to membrane receptors, that frequently do not involve changes in gene transcription (13). GPER represents a third ER in addition to the classical nuclear ER isoforms ER· and ERß. GPER, previously known as GPR30, has been cloned by several research groups initially as an orphan G-protein coupled receptor (GPCR) with a wide distribution in both reproductive and nonreproductive tissues (14-17). Filardo and co-workers suggested that GPER may be associated with estrogen signalling based on their finding that estrogens caused rapid activation of signalling pathways in a breast cancer cell line (SKBR3 cells) that do not express ERs but express GPER (18). Subsequently it was demonstrated independently by two research groups that recombinan...

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Section: Discussionsupporting

confidence: 83%

G-protein coupled estrogen receptor 1 expression in rat and human heart: Protective role during ischaemic stress

Patel

Chen²,

Ramanjaneya³

et al. 2010

Int J Mol Med

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“…Indeed, using both a chemical inhibitor and siRNA-mediated knockdown of AMPK, we demonstrated that AMPK is required for 2-DG to provide protection against DOX cardiotoxicity, suggesting that therapeutic strategies aiming to increase AMPK activity would be expected to reduce DOX cardiotoxicity. In this respect, metformin, a commonly prescribed drug for type 2 diabetes, is able to protect the heart under various pathological conditions (82)(83)(84)(85)(86)(87). It can also enhance the ability of DOX to reduce tumor mass (88).…”

Section: Discussionmentioning

confidence: 99%

Caloric Restriction Mimetic 2-Deoxyglucose Antagonizes Doxorubicin-induced Cardiomyocyte Death by Multiple Mechanisms

Chen

Kobayashi³

et al. 2011

Journal of Biological Chemistry

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Caloric restriction (CR) is a dietary intervention known to enhance cardiovascular health. The glucose analog 2-deoxy-Dglucose (2-DG) mimics CR effects in several animal models. However, whether 2-DG is beneficial to the heart remains obscure. Here, we tested the ability of 2-DG to reduce cardiomyocyte death triggered by doxorubicin (DOX, 1 M), an antitumor drug that can cause heart failure. Treatment of neonatal rat cardiomyocytes with 0.5 mM 2-DG dramatically suppressed DOX cytotoxicity as indicated by a decreased number of cells that stained positive for propidium iodide and reduced apoptotic markers. 2-DG decreased intracellular ATP levels by 17.9%, but it prevented DOX-induced severe depletion of ATP, which may contribute to 2-DG-mediated cytoprotection. Also, 2-DG increased the activity of AMP-activated protein kinase (AMPK). Blocking AMPK signaling with compound C or small interfering RNA-mediated knockdown of the catalytic subunit markedly attenuated the protective effects of 2-DG. Conversely, AMPK activation by pharmacological or genetic approach reduced DOX cardiotoxicity but did not produce additive effects when used together with 2-DG. In addition, 2-DG induced autophagy, a cellular degradation pathway whose activation could be either protective or detrimental depending on the context. Paradoxically, despite its ability to activate autophagy, 2-DG prevented DOX-induced detrimental autophagy. Together, these results suggest that the CR mimetic 2-DG can antagonize DOX-induced cardiomyocyte death, which is mediated through multiple mechanisms, including the preservation of ATP content, the activation of AMPK, and the inhibition of autophagy.

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“…Experimental studies have previously established that the antidiabetic agents insulin and metformin can confer cardioprotection in animal MI models (Bhamra et al, 2008;Whittington et al, 2013a). Some of the newer antidiabetic agents have also been reported to limit infarct size in the diabetic and nondiabetic heart, including 1) thiazolidinediones, such as rosiglitazone (Morrison et al, 2011;Palee et al, 2013) and pioglitazone (Ye et al, 2008;; 2) GLP-1 analogs, such as liraglutide (Noyan-Ashraf et al, 2009) and exenatide (Timmers et al, 2009); and 3) dipeptidyl peptidase-4 inhibitors, such as sitagliptin (Sauve et al, 2010;Ye et al, 2010a;Hausenloy et al, 2013b) and vildagliptin .…”

Section: Antidiabetic Therapymentioning

confidence: 99%

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

Ferdinándy¹,

Hausenloy²,

Heusch³

et al. 2014

Pharmacol Rev

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Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening

Cited by 185 publications

References 54 publications

G-protein coupled estrogen receptor 1 expression in rat and human heart: Protective role during ischaemic stress

G-protein coupled estrogen receptor 1 expression in rat and human heart: Protective role during ischaemic stress

Caloric Restriction Mimetic 2-Deoxyglucose Antagonizes Doxorubicin-induced Cardiomyocyte Death by Multiple Mechanisms

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

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