Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS

Hickson-Bick, Diane L.; Sparagna, Genevieve C.; Buja, L. Maximilian; McMillin, Jeanie B.

doi:10.1152/ajpheart.00726.2001

Cited by 97 publications

(75 citation statements)

References 32 publications

(29 reference statements)

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“…Our findings that PA induced caspase 3 activity in LA-4 cells, and either OA or LA attenuated PA-induced caspase 3 activity, are consistent with the previous reports described in a variety of cell types [29][30][31][32][33][34][35] . Therefore, we hypothesize that the increased apoptosis of alveolar type II epithelial cells in Elovl6 À / À mice is attributable to an increase in C16 PA and/or a decrease in C18 OA and C18 LA within the cells.…”

Section: Blm Treatment Decreases Elovl6 Expression In the Lungsupporting

confidence: 93%

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

et al. 2013

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Despite the established role of alveolar type II epithelial cells for the maintenance of pulmonary function, little is known about the deregulation of lipid composition in the pathogenesis of pulmonary fibrosis. The elongation of long-chain fatty acids family member 6 (Elovl6) is a rate-limiting enzyme catalysing the elongation of saturated and monounsaturated fatty acids. Here we show that Elovl6 expression is significantly downregulated after an intratracheal instillation of bleomycin (BLM) and in human lung with idiopathic pulmonary fibrosis. Elovl6-deficient (Elovl6 À / À ) mice treated with BLM exhibit severe fibroproliferative response and derangement of fatty acid profile compared with wild-type mice. Furthermore, Elovl6 knockdown induces a change in fatty acid composition similar to that in Elovl6 À / À mice, resulting in induction of apoptosis, TGF-b1 expression and reactive oxygen species generation. Our findings demonstrate a previously unappreciated role for Elovl6 in the regulation of lung homeostasis, and in pathogenesis and exacerbation of BLM-induced pulmonary fibrosis.

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Section: Blm Treatment Decreases Elovl6 Expression In the Lungsupporting

confidence: 93%

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

et al. 2013

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“…Open bar, control of cardiomyocytes with 1 mmol/l palmitic acid lowered, rather than increased ROS levels. This observation is consistent with previous studies, which suggest that a high concentration of palmitic acid decreases mitochondrial membrane potential, and the ability of the mitochondria to produce ROS [34,35]. Provision of a low concentration of metformin (1 or 2 mmol/l) restored ROS to control levels, probably due to the effect of metformin in promoting fatty acid oxidation and electron flow through the mitochondrial electron transport chain [35].…”

Section: Discussionsupporting

confidence: 92%

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

et al. 2006

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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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“…Thus, it appears that the ␤-oxidation pathway and the generation of ROS are not implicated in the cell death process caused by palmitate in MDA-MB-231 cells. ROS were also shown not to be implicated in palmitate induced-apoptosis in cardiomyocytes (45).…”

Section: Discussionmentioning

confidence: 95%

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

Hardy

El-Assaad

Przybytkowski

et al. 2003

Journal of Biological Chemistry

248

243

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Little is known about the biochemical basis of the action of free fatty acids (FFA) on breast cancer cell proliferation and apoptosis. Here we report that unsaturated FFAs stimulated the proliferation of human MDA-MB-231 breast cancer cells, whereas saturated FFAs inhibited it and caused apoptosis. Saturated FFA palmitate decreased the mitochondrial membrane potential and caused cytochrome c release. Palmitate-induced apoptosis was enhanced by the fat oxidation inhibitor etomoxir, whereas it was reduced by fatty-acyl CoA synthase inhibitor triacsin C. The non-metabolizable analog 2-bromopalmitate was not cytotoxic. This indicates that palmitate must be metabolized to exert its toxic effect but that its action does not involve fat oxidation. Pharmacological studies showed that the action of palmitate is not mediated via ceramides, reactive oxygen species, or changes in phosphatidylinositol 3-kinase activity. Palmitate caused early enhancement of cardiolipin turnover and decreased the levels of this mitochondrial phospholipid, which is necessary for cytochrome c retention. Cosupplementation of oleate, or increasing ␤-oxidation with the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-␤-D-ribonucleoside, both restored cardiolipin levels and blocked palmitate-induced apoptosis. Oleate was preferentially metabolized to triglycerides, and oleate cosupplementation channeled palmitate esterification processes to triglycerides. Overexpression of Bcl-2 family members blocked palmitateinduced apoptosis. The results provide evidence that a decrease in cardiolipin levels and altered mitochondrial function are involved in palmitate-induced breast cancer cell death. They also suggest that the antiapoptotic action of oleate on palmitate-induced cell death involves both restoration of cardiolipin levels and redirection of palmitate esterification processes to triglycerides.

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Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS

Cited by 97 publications

References 32 publications

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

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