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In vitro folate supplementation alleviates oxidative stress, mitochondria-associated death signalling and apoptosis induced by 7-ketocholesterol

Published online by Cambridge University Press:  09 March 2007

R.-F. S. Huang ,
H.-C. Yaong ,
S.-C. Chen  and
Y.-F. Lu
R.-F. S. Huang*
Affiliation:
Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, Republic of China
H.-C. Yaong
Affiliation:
Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, Republic of China
S.-C. Chen
Affiliation:
Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, Republic of China
Y.-F. Lu
Affiliation:
Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, Republic of China
*
*Corresponding author: Dr R.-F. S. Huang, fax +86 2 29021215, email, [email protected]
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Abstract

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Folate has recently been proposed as a new antioxidant. Folate supplementation may have a protective effect in counteracting oxidant-induced apoptotic damage. The present studies were undertaken to examine whether there is a direct link between folate levels, antioxidant capability and reduced apoptotic damage. Using an in vitro cellular model of 7-ketocholesterol (KC)-induced apoptosis, U937 cells were pre-cultured with a folate-deficient medium supplemented with various levels of folate (2–1500μmol/l) before treatment with 7-KC. Apoptotic markers, mitochondria-associated death signals and levels of reactive oxygen species were assayed. After treatment with 7-KC for 30h, low and high levels of folate supplementation significantly (P<0.05) reduced nuclear DNA loss. Only high levels of folate supplementation (>1000μmol/l) were effective in counteracting 7-KC-promoted apoptotic membrane phosphatidylserine exposure and DNA laddering. The attenuation of 7-KC-induced apoptotic damage by high-dose folate supplementation coincided with a partial normalization of mitochondria membrane potential dissipation, a suppression of cytochrome c release and an inhibition of procaspase 3 activation. The prevention of mitochondrial dysfunctions and apoptotic processes was associated with antioxidant actions of high-dose folate by a marked scavenging of intracellular superoxide. Collectively, our present results demonstrate that in vitro folate supplementation exerts differentially protective effects against 7-KC-induced damage. High-dose supplementation alleviates oxidative stress, mitochondria-associated death signalling and apoptosis induced by 7-KC. However, the in vivo relevance is not clear and requires further study.

Keywords

Folate supplementationAntioxidantApoptosisMitochondria-associated death signalling7-Ketocholesterol
Type
Review Article
Information
British Journal of Nutrition , Volume 92 , Issue 6 , December 2004 , pp. 887 - 894
Copyright
Copyright © The Nutrition Society 2004

References

Aupeix, K, Weltin, D, Mejia, JE, Christ, M, Marchal, J, Freyssinet, JM & Bischoff, P (1995) Oxysterol-induced apoptosis in human monocytic cell lines. Immunobiol 194, 415–428.CrossRefGoogle ScholarPubMed
Bernardi, P, Petronilli, V, Lisa, FD & Forte, M (2001) A mitochondrial perspective on cell death. Trends Biochem Sci 26, 112–117.CrossRefGoogle ScholarPubMed
Brookes, PS & Baggott, JE (2002) Oxidation of 10-formyltetrahydrofolate to 10-formyldihydrofolate by complex IV of rat mitochondria. Biochem 41, 5633–5636.CrossRefGoogle ScholarPubMed
Brown, AJ, Leong, SL, Dean, RT & Jessup, W (1997) 7-Hydroperoxycholesterol and its products in oxidized low density lipoprotein and human atherosclerotic plaque. J Lipid Res 38, 1730–1745.CrossRefGoogle ScholarPubMed
Cai, J & Jones, DP (1998) Superoxide in apoptosis. J Biol Chem 273, 11401–11404.CrossRefGoogle ScholarPubMed
Calver, JF, Hill, JL & Dong, A (1997) Redox-dependent conformational changes are common structural features of cytochrome c from various species. Arch Biochem Biophys 346, 287–293.CrossRefGoogle Scholar
Chandra, J, Samali, A & Orrenius, S (2000) Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 29, 323–333.CrossRefGoogle ScholarPubMed
Chang, CM (2004), Effects of folate supplementation on mitochondrial DNA deletion, function and oxidative damage in rat liver, MSc Thesis, Fu-Jen University, TaiwanGoogle Scholar
Chen, YH, Huang, RFS, Wei, JS & Liu, TZ (2001) Folate deficiency-mediated down regulation of intracellular glutathione and antioxidant enzymes increases susceptibility of human hepatoma HepG2 cells to various oxidant stress-induced cytotoxicity. J Biomed Lab Sci 13, 52–57.Google Scholar
Chern, CL, Huang, RFS, Chen, YH, Cheng, JT & Liu, TZ (2001) Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhances activation of NF-κB in human HepG2 cells. Biomed Pharmacother 55, 434–442.CrossRefGoogle Scholar
Craciunescu, CN, Brown, EC, Mar, MH, Albright, CD, Nadeau, MR & Zeisel, SH (2004) Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr 134, 162–166.CrossRefGoogle ScholarPubMed
Crompton, M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341, 233–249.CrossRefGoogle ScholarPubMed
Doshi, SN, McDowell, IFW, Moat, SJ, Lang, D, Newcombe, RG, Kredan, MB, Lewis, MJ & Goodfellow, J (2001) Folate improves endothelial function in coronary artery disease. An effect mediated by reduction of intracellular superoxide?. Arterioscler Thromb Vasc Biol 21, 1196–1202.CrossRefGoogle ScholarPubMed
Duan, W, Ladenheim, B, Cutler, RG, Kruman, II, Cadet, JL & Mattson, MP (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neuron in models of Parkinson's disease. J Neurochem 80, 101–110.CrossRefGoogle ScholarPubMed
Endresen, PC, Prytz, PS, Lysne, S & Aarbakke, J (1994) Homocysteine increases the relative number of apoptotic cells and reduces the relative number of apoptotic bodies in HL-60 cells treated with 3-deazaadenosine. J Pharmacol Exp Ther 269, 1245–1253.Google ScholarPubMed
Garcia-Cruset, S, Carpenter, KL, Guardiola, F & Mitchinson, MJ (1999) Oxysterols in core of human advanced atherosclerotic lesions. Free Radic Res 30, 341–350.CrossRefGoogle ScholarPubMed
Granville, DJ, Carthy, CM, Hunt, DWC & McManus, BM (1998) Apoptosis: molecular aspects of cell death and disease. Lab Invest 78, 893–913.Google Scholar
Gu, L, Wu, J, Qiu, L, Jennings, CD & Li, GM (2002) Involvement of DNA mismatch repair in folate deficiency-induced apoptosis. J Nutr Biochem 13, 355–363.CrossRefGoogle ScholarPubMed
Han, DKM, Haudenschild, CC, Hong, MK, Tinkle, BT, Leon, MB & Liau, G (1995) Evidence for apoptosis in human atherogenesis and in rat injury model. Am J Pathol 147, 267–277.Google Scholar
Hancock, JT, Desikan, R & Neill, SJ (2001) Does the redox status of cytochrome c act as a fall-safe mechanism in the regulation of programmed cell death?. Free Radic Biol Med 31, 697–703.CrossRefGoogle Scholar
Horne, DW, Patterson, D & Cook, RJ (1989) Effect of nitrous oxide inactivation of vitamin B12 -dependent methionine synthestase on the subcellular distribution of folate coenzymes in rat liver. Arch Biochem Biophys 270, 729–733.CrossRefGoogle Scholar
Huang, RFS, Ho, YH, Lin, HL, Wei, JS & Liu, TZ (1999) Folate deficiency induces a cell cycle-specific apoptosis in HepG2 cells. J Nutr 129, 25–31.CrossRefGoogle ScholarPubMed
Huang, RFS, Hsu, YC, Lin, HL & Yang, FL (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 131, 33–38.CrossRefGoogle ScholarPubMed
Huang, RFS, Huang, SM, Lin, BS, Hung, CY & Lu, HT (2002) N -acetylcysteine, vitamin C and vitamin E diminish homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. J Nutr 132, 2151–2155.CrossRefGoogle ScholarPubMed
Isner, JM, Kearney, M, Bortman, S & Psseri, J (1995) Apoptosis in human atherosclerosis and restenosis. Circulation 91, 2703–2711.CrossRefGoogle ScholarPubMed
James, SJ, Barbara, JM, Basnakian, AG, Pogribny, IP, Pogribna, M & Muskhelishvili, L (1997) Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis 18, 287–293.CrossRefGoogle ScholarPubMed
James, SJ, Basnakian, AG & Miller, BJ (1994) In vitro folate deficiency induces deoxynucleotide pool imbalance, apoptosis, and mutagenesis in Chinese hamster ovary cells. Cancer Res 54, 5075–5080.Google ScholarPubMed
Joshi, R, Adhikari, S, Patro, BS, Chattopadhyay, S & Mukherjee, T (2001) Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic Biol Med 30, 1390–1399.CrossRefGoogle ScholarPubMed
Juan, G, Cavazzoni, M, Saez, GT, O'Connor, JE (1994) A fast kinetic method for assessing mitochondrial membrane potential in isolated hepatocytes with rhodamine 123 and flow cytometry. Cytometry 15, 335–342.CrossRefGoogle ScholarPubMed
Kim, YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10, 66–88.CrossRefGoogle ScholarPubMed
Koury, MJ, Horne, DW, Brown, ZA, Pietenpol, JA, Blount, BC, Ames, BN, Hard, R & Koury, ST (1997) Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood 89, 4617–4623.CrossRefGoogle ScholarPubMed
Kroemer, G, Petit, P, Zamzami, N, Vayssiere, J & Mignotte, B (1995) The biochemistry of programmed cell death. FASEB J 9, 1277–1287.CrossRefGoogle ScholarPubMed
Kroemer, G, Zazami, N & Susin, SA (1997) Mitochondrial control of apoptosis. Immunol Today 18, 44–51.CrossRefGoogle ScholarPubMed
Li, P, Nijhawan, D, Budihardjo, I, Srinivasula, SM, Ahmad, M, Alnemri, ES & Wang, X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489.CrossRefGoogle ScholarPubMed
Lim, MLR, Lum, MG, Hansen, TM, Roucou, X & Nagley, P (2002) On the release of cytochrome c from mitochondria during cell death signaling. J Biomed Sci 9, 488–506.Google ScholarPubMed
Lizard, G, Deckert, V, Duberz, L, Moisant, M, Gambert, P & Lagrost, L (1996) Induction of apoptosis in endothelial cells treated with cholesterol oxides. Am J Pathol 148, 1625–1638.Google ScholarPubMed
Lizard, G, Gueldry, S, Sordet, O, Monier, S, Athias, A, Miguet, C, Bessede, G, Lemaire, S, Solary, E & Gambert, P (1998) Glutathione is implied in the control of 7-ketocholesterol-induced apoptosis, which is associated with radical oxygen species production. FASEB J 12, 1651–1663.CrossRefGoogle ScholarPubMed
Lizard, G, Miguet, C, Bessede, G, Monier, S, Gueldry, S, Neel, D & Gambert, P (2000) Impairment with various antioxidants of the loss of mitochondrial transmembrane potential and of the cytosolic release of cytochrome c occurring during 7-ketocholesterol-induced apoptosis. Free Radic Biol Med 28, 743–753.CrossRefGoogle ScholarPubMed
Lizard, G, Moisant, M, Cordelet, C, Monier, S, Gambert, P & Lagrost, L (1997) Induction of similar features of apoptosis in human and bovine vascular endothelial cells treated by 7-ketocholesterol. J Pathol 183, 330–338.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
Lizard, G, Monier, S, Cordelet, C, Gesquiere, L, Deckert, V, Gueldry, S, Lagrost, L & Gambert, L (1999) Characterization and comparison of the mode of cell death, apoptosis versus necrosis, induced by 7α-hydroxycholesterol and 7-ketocholesterol on the cells of the vascular wall. Arterioscler Thromb Vasc Biol 19, 1190–2000.CrossRefGoogle ScholarPubMed
Nishio, E, Arimura, S & Watanabe, Y (1996) Oxidized LDL induces apoptosis in cultured smooth muscle cells: a possible role for 7-ketocholesterol. Biochem Biophys Res Commun 223, 413–418.CrossRefGoogle ScholarPubMed
Nishio, E & Watanabe, Y (1996) Oxysterols induced apoptosis in cultured smooth muscle cells through CPP32 protease activation and bcl-2 protein downregulation. Biochem Biophys Res Commun 226, 928–934.CrossRefGoogle ScholarPubMed
O‘Callaghan, YC, Woods, JA, O’Brien, NM (2001) Comparative study of the cytotoxicity and apoptosis-inducing potential of commonly occurring oxysterols. Cell Biol Toxicol 17, 127–137.CrossRefGoogle ScholarPubMed
Palmer, HJ & Paulson, KE (1997) Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr Rev 55, 353–361.CrossRefGoogle ScholarPubMed
Robinson, JP, Carter, WO & Narayanan, PK (1994) Oxidative product formation analysis by flow cytometry. Methods Cell Biol 41, 437–447.CrossRefGoogle ScholarPubMed
Sprecher, H, Barr, HM, Slotky, JI, Tzukerman, M, Eytan, GD & Assaraf, YG (1995) Alteration of mitochondrial gene expression and disruption of respiratory function by the lipophilic antifolate pyrrimethamine in mammalian cells. J Biol Chem 270, 20668–20676.CrossRefGoogle ScholarPubMed
Stridh, H, Kimland, M, Jones, DP, Orrenius, S & Hampton, MB (1998) Cytochrome c release and caspase activation in hydrogen peroxide- and tributyltin-induced apoptosis. FEBS Lett 429, 351–355.CrossRefGoogle ScholarPubMed
Tada-Oikawa, S, Oikawa, S, Kawanishi, M, Yamada, M & Kawanishi, S (1999) Generation of hydrogen peroxide precedes loss of mitochondrial membrane potential during DNA alkylation-induced apoptosis. FEBS Lett 442, 65–69.CrossRefGoogle ScholarPubMed
Title, LM, Cummings, PM, Giddens, K, Genest, JJ Jr & Nassar, BA (2000) Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 36, 758–765.CrossRefGoogle ScholarPubMed
Zamzami, N & Kroemer, G (2001) The mitochondrion in apoptosis: how Pandora's box opens. Nat Rev Mol Cell Biol 2, 67–71.CrossRefGoogle ScholarPubMed