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Title:
Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3 | Diabetologia
Description:
Aims/hypothesis Metformin has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). We hypothesised that metformin could prevent both caspase-3 activation and apoptosis when induced by palmitic acid. Materials and methods Cardiomyocytes were incubated with 1 mmol/l palmitic acid, in the absence or presence of metformin (1–5 mmol/l). Following 1 to 16 h, cell damage was evaluated by measuring lactate dehydrogenase released into the incubation medium, and Hoechst staining. To investigate the mechanism of metformin’s effect on cardiomyocytes, substrate utilisation and phosphorylation of AMPK and acetyl-CoA carboxylase were measured. Intracellular mediators of apoptosis were also evaluated. Results Incubation of myocytes with palmitic acid for 16 h increased apoptosis, an effect that was partly blunted by 1 and 2 mmol/l metformin. This beneficial effect of metformin was associated with increased AMPK phosphorylation, palmitic acid oxidation and suppression of high-fat-induced increases in (1) long chain base biosynthesis protein 1 levels, (2) ceramide levels, and (3) caspase-3 activity. Unexpectedly, 5 mmol/l metformin dramatically increased apoptosis in myocytes incubated with high fat. This effect was associated with a robust increase in glycolysis, lactate accumulation, and a significant drop of pH in the myocyte incubation medium. Conclusions/interpretation Our study demonstrates that metformin reduces high-fat-induced cardiac cell death, probably through inhibition of ceramide synthesis. However, at high concentrations, metformin causes proton and lactate accumulation, leading to cell damage that is independent of caspase-3.
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Keywords {🔍}
metformin, acid, mmoll, article, pubmed, google, scholar, cas, apoptosis, cell, fatty, protein, ceramide, oxidation, ampk, fig, palmitic, activation, cardiomyocytes, diabetes, glucose, caspase, incubation, death, medium, control, high, cells, glycolysis, ldh, kinase, lactate, increased, release, incubated, difference, ros, effect, data, myocytes, highfatinduced, cardiomyocyte, phosphorylation, activity, heart, measured, levels, fat, usa, absence,
Topics {✒️}
high-fat-induced cell death amp-activated protein kinase study high-fat-induced apoptosis hickson-bick dl secondary goat anti-rabbit palmitate-induced cardiomyocyte apoptosis high-fat-induced increases high-fat-induced apoptotic cells high-fat-induced lcb-1 reactive oxygen species nitric oxide-induced apoptosis fluorescent dna-binding dye fatty acid-induced apoptosis 5% octyl-β-d-glucoside high-fat-induced activation exercise-induced metabolic acidosis sds-polyacrylamide gel electrophoresis exogenous c2-ceramide mimics albumin-bound palmitic acid glucose fatty-acid cycle magnesium-dependent neutral sphingomyelinase high-fat-treated group hyperglycemia-induced apoptosis cell death induced palmitate-induced apoptosis preventing cell death long lcb1 antibodies 32p-labelled ceramide 1-phosphate mitochondrial redox state malonyl-coa levels due nitric oxide signaling caspase-3 article published stimulates glucose uptake prevent cell death promotes mitochondrial biogenesis graduate research scholarships increased lcb1 protein privacy choices/manage cookies cardiac lcb1 expression cyclophosphamide-induced cardiotoxicity fatty acids accumulate altered glucose transport rat cardiac camp calcium-tolerant myocardial cells palmitate-mediated alterations promotes fatty acid fatty acid oxidation increasing mitochondrial cytochrome fatty acid spillover carnitine palmitoyl transferase-1
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headline:Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3
description:Metformin has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). We hypothesised that metformin could prevent both caspase-3 activation and apoptosis when induced by palmitic acid. Cardiomyocytes were incubated with 1 mmol/l palmitic acid, in the absence or presence of metformin (1–5 mmol/l). Following 1 to 16 h, cell damage was evaluated by measuring lactate dehydrogenase released into the incubation medium, and Hoechst staining. To investigate the mechanism of metformin’s effect on cardiomyocytes, substrate utilisation and phosphorylation of AMPK and acetyl-CoA carboxylase were measured. Intracellular mediators of apoptosis were also evaluated. Incubation of myocytes with palmitic acid for 16 h increased apoptosis, an effect that was partly blunted by 1 and 2 mmol/l metformin. This beneficial effect of metformin was associated with increased AMPK phosphorylation, palmitic acid oxidation and suppression of high-fat-induced increases in (1) long chain base biosynthesis protein 1 levels, (2) ceramide levels, and (3) caspase-3 activity. Unexpectedly, 5 mmol/l metformin dramatically increased apoptosis in myocytes incubated with high fat. This effect was associated with a robust increase in glycolysis, lactate accumulation, and a significant drop of pH in the myocyte incubation medium. Our study demonstrates that metformin reduces high-fat-induced cardiac cell death, probably through inhibition of ceramide synthesis. However, at high concentrations, metformin causes proton and lactate accumulation, leading to cell damage that is independent of caspase-3.
datePublished:2006-07-26T00:00:00Z
dateModified:2006-07-26T00:00:00Z
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AMPK
Apoptosis
Cardiomyocyte
Metformin
Palmitic acid
Internal Medicine
Metabolic Diseases
Human Physiology
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headline:Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3
description:Metformin has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). We hypothesised that metformin could prevent both caspase-3 activation and apoptosis when induced by palmitic acid. Cardiomyocytes were incubated with 1 mmol/l palmitic acid, in the absence or presence of metformin (1–5 mmol/l). Following 1 to 16 h, cell damage was evaluated by measuring lactate dehydrogenase released into the incubation medium, and Hoechst staining. To investigate the mechanism of metformin’s effect on cardiomyocytes, substrate utilisation and phosphorylation of AMPK and acetyl-CoA carboxylase were measured. Intracellular mediators of apoptosis were also evaluated. Incubation of myocytes with palmitic acid for 16 h increased apoptosis, an effect that was partly blunted by 1 and 2 mmol/l metformin. This beneficial effect of metformin was associated with increased AMPK phosphorylation, palmitic acid oxidation and suppression of high-fat-induced increases in (1) long chain base biosynthesis protein 1 levels, (2) ceramide levels, and (3) caspase-3 activity. Unexpectedly, 5 mmol/l metformin dramatically increased apoptosis in myocytes incubated with high fat. This effect was associated with a robust increase in glycolysis, lactate accumulation, and a significant drop of pH in the myocyte incubation medium. Our study demonstrates that metformin reduces high-fat-induced cardiac cell death, probably through inhibition of ceramide synthesis. However, at high concentrations, metformin causes proton and lactate accumulation, leading to cell damage that is independent of caspase-3.
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Apoptosis
Cardiomyocyte
Metformin
Palmitic acid
Internal Medicine
Metabolic Diseases
Human Physiology
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