Abstract
While Ca2+ has been proposed to be a messenger in OxLDL-induced cell death, few studies have addressed the possibility that it may influence the occurrence of apoptosis and necrosis of macrophages induced by OxLDL in virtue of change of transmembrane Ca2+ gradient including that across plasma membrane and intracellular organelle membranes. In this paper, various lipophilic Ca2+ fluorescent indicators and specific organelle markers were used to study the relationship between the changes of the transmembrane Ca2+ gradients and the OxLDL induced apoptosis of macrophages. Our results showed that following exposure of low dose OxLDL to macrophages, the transmembrane Ca2+ gradient across the plasma membrane, as well as the membrane-proximal Ca2+ gradient, the transnuclear, and the transmitochondrial membrane Ca2+ gradient were all changed significantly. These data suggested that changes in transmembrane Ca2+ gradients might be involved in the apoptosis of macrophages induced by OxLDL.
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REFERENCES
Carafoli, E. (1987) Intracellular Calcium Homeostasis. Ann. Reû. Biochem. 56: 395–433.
Mooren, F. C. (1998) Kinne RKH Cellular calcium in health and disease. Biochim. Biophys. Acta 1406: 127–151.
Brown, E. M. Vassiler, P. M., and Herbert, S. C. (1995) Ca2??ions as extracellular messengers. Cell 83: 679–682.
Yang, F. Y., Huang, Y. G., and Tu, Y. P. (1995) Transmembrane Ca2??gradient and function of membrane proteins. Biooscience Rep. 15: 351–364.
Yang, X. Y., Fan, G. F., Huang, Y. G., and Yang, F. Y. (1996) Effect of transmembrane Ca2??gradient on ligand binding of reconstituted ????????adrenergic receptors. Chinese Science Bulletin 41: 1214–1218.
Fan, G. F., Huang, Y. G., Bai, Y. H., and Yang, F. Y. (1994) Effect of transmembrane Ca2??gradient on Gs function. FEBS Lett. 357: 13–15.
Fan, G. F., Yang, X. Y., Huang, Y. G., and Yang, F. Y. (1996) Effect of transmembrane Ca2??gradient on the coupling of ????????drenergic receptors and adenylyl cyclase. Bioscience Rep. 16: 327–341.
Yang, X. Y., Fan, G. F., Huang, Y. G., and Yang, F. Y. (1996) Effect of transmembrane Ca2??gradient on ligand binding of reconstituted ????????adrenergic receptors. Chinese Science Bulletin 41: 1214–1218.
Mitchinson, M. J., Hardwick, S. J., and Bennett, M. R. (1996) Cell death in atherosclerotic plaques. Curr. Opin. Lipidol. 7: 324–329.
Geng, Y. J. (1997) Regulation of programmed cell death or apoptosis in atherosclerosis. Heart Vessels 12 (Suppl): 76–80.
Bjorkerud, S. and Bjorerud, B. (1996) Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am. J. Pathol. 149: 367–380.
Meilhac, O., Escargueil-Blanc, I., Thiers, J. C., Salvayre, R., and Negre-Salvayre, A. (1999) Bcl-2 alters the balance between apoptosis and necrosis, but does not prevent cell death induced by oxidized low density lipoproteins. FASEB J. 13: 485–494.
Reid, V. C. and Mitchinson, M. J. (1993) Toxicity of oxidized low density lipoprotein towards mouse peritoneal macrophages in ûitro. Atherosclerosis 98: 17–24.
Reid, V. C., Hardwick, S. J., and Mitchinson, M. J. (1993) Fragmentation of DNA in P388D1 macrophages exposed to oxidized low-density lipoprotein. FEBS Lett. 332: 218–220.
Reid, V. C., Mitchinson, M. J., and Skepper, J. N. (1993) Cytotoxicity of oxidized low-density lipoprotein to mouse peritoneal macrophages: an ultrastructural study. J. Pathol. 171: 321–328.
Kinscherf, R. et al. (1998) Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J. 12: 461–467.
Stewart-Phillips, J. L., Lough, J., and Skamene, E. (1988) Genetically determined susceptibility and resistance to diet-induced atherosclerosis in inbred strains of mice. J. Lab. Clin. Med. 112: 36–42.
Paigen, B., Morrow, A., Brandon, C., Mitchell, D., and Holmes, P. (1985) Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57: 65–73.
Havel, R. I., Eder, H. A., and Braigon, J. H. (1955) The distribution and the chemical composition of ultracentrifugally separated lipoproteins in human serum. J. Clin. Inûest. 39: 1345–1363.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193: 265–275.
Kosugi, K., Morel, D. W., and DiCorleto, P. E., (1987) Chisholm GM Toxicity of oxidized LDL to cultured fibroblasts is selective for S phase of the cell cycle. J. Cell Physiol. 130: 311–320.
Yagi, K. (1985) Lipid peroxides and human diseases. Chem. Phys. Lipids 45: 337–351.
Rees, D., Sloane, T., Jessup, W., and Dean, R. T. (1999) Kritharides L Apolipoprotein A-I stimulates secretion of apolipoprotein E by foam cell macrophages. J. Biol. Chem. 274: 27925–27933.
Dive, C., Gregory, C. D., Phipps, D. J., Evans, D. L., Milner, A. E., and Wyllie, A. H. (1992) Analysis and discrimination of necrosis and apoptosis (programmed cell death) by multiparameter flow cytometry. Biochim. Biophys. Acta. 1133: 275–285.
Darzynkiewicz, Z., et al. (1992) Features of apoptotic cells measured by flow cytometry. Cytometry 13: 795–808.
Lloyd, Q. P., Kuhn, M. A., and Gay, C. V. (1995) Characterization of calcium translocation across the plasma membrane of primary osteoblasts using a lipophilic calcium-sensitive fluorescent dye, calcium green C??. J. Biol. Chem. 270: 22445–22451.
Tanimura, A. and Turner, R. J. (1996) Inositol 1,4,5-triphosphate-dependent oscillations of luminal [Ca2?] in permeabilized HSY cells. J. Biol. Chem. 271: 30904–30908.
Donnadieu, E. and Bourguignon, L. Y. W. (1996) Ca2??signaling in endothelial cells stimulated by bradykinin: Ca2??measurement in the mitochondria and the cytosol by confocal microscopy. Cell Calcium 20: 53–61.
Yang, X. Y., Yan, K., and Huang, Y. G. (1996) A powerful method for the determination of the spatial and temporal changes of intracellular Ca2??in single macrophages by laser Scanning Confocal Microscopy. Prog. Biochem. Biophys. 23: 442–445.
Hernandez-Cruz, A., Sala, F., and Adams, P. R. (1990) Subcellular calcium transients visualized by confocal microscopy in a voltage-clamped vertebrate neuron. Science 247: 858–862.
Herrington, J., Park, Y. B., Babcock, D. F., and Hille, B. (1996) Dominant role of mitochondria in clearance of large Ca2??loads from rat adrenal chromaffin cells. Neuron 16: 219–228.
Park, Y. B., Herrington, J., Babcock, D. F., and Hille, B. (1996) Ca2??clearance mechanisms in isolated rat adrenal chromaffin cells. J. Physiol. 492: 329–346.
Grynkiewicz, G., Poenie, M., and Tsien, R. Y. (1985) A new generation of Ca2??indiatrs with greatly improved fluorescence properties. J. Biol. Chem. 260: 3440–3450.
Eberhard, M. and Erne, P. (1991) Calcium binding to fluorescent calcium indicators: calcium green, calcium orange and calcium crimson. Biochem. Biophys. Res. Commun. 180: 209–215.
Ylitalo, R., Jaakkola, O., Lehtolainen, P., and Yla-Herttuala, S. (1999) Metabolism of modified LDL and form cell formation in murine macrophage-like RAW 264 cells. Life Sci. 64: 1955–1965.
Yang, X. Y., Zhong, Y. Z., Huang, Y. G., and Yang, F. Y. (2000) Changes of transmembrane Ca2??gradient in the formation of macrophage-derived foam cells. Biosci. Rep. 20: 1–12.
Etter, E. F., Kuhn, M. A., and Fay, F. S. (1994) Detection of changes in near-membrane Ca2??concentration using a novel membrane-associated Ca2??indicator. J. Biol. Chem. 269: 10141–10149.
Etter, E. F., Minta, A., Poenie, M., and Fay, F. S. (1996) Near-membrane [Ca2?] transients resolved using the Ca2??indicator FFP18. Proc. Natl. Acad. Sci. USA 93: 5368–5373.
Davies, E. V. and Hallet, M. B. (1996) Near membrane Ca2??changes resulting from store release in neutrophils: detection by FFP-18. Cell Calcium 19: 355–362.
Tojyo, Y., Tanimura, A., and Matsumoto, Y. (1997) Monitoring of Ca2??release from intracellular stores in permeabilized rat parotid acinar cells using the fluorescent indicators Mag-fura-2 and calcium green C??. Biochem. Biophys. Res. Commun. 240: 189–195.
Lin, C. P., Lynch, M. C., and Kochevar, I. E. (2000) Reactive oxidizing species produced near the plasma membrane induce apoptosis in bovine aorta endothelial cells. Exp. Cell Res. 259: 351–359.
Yang, X. Y., Tan, J. M., Huang, Y. G., and Yang, F. Y. (1997) The correlation of transmembrane Ca2??gradients and Ca2??oscillation in single macrophages. Prog. Natural Sciences 7: 438–442.
Santella, L. and Carafoli, E. (1997) Calcium signaling in the cell nucleus. FASEB J. 11: 1091–1109.
Himpens, B., De Smedt, H., Droogmans, G., and Casteels, R. (1992). Differences in regulation between the nuclear and cytoplasmic Ca2??in DDT1MF2 smooth muscle cells. Am. J. Physiol. 263: C95-C105.
Himpens, B., Missiaen, L., and Casteels, R. (1995) Ca2??homeostasis in vascular smooth muscle. J. Vasc. Res. 32: 207–219.
Himpens, S., De Smedt, H., and Casteels, R. (1994) Relationship between [Ca2?] changes in nucleus and cytosol. Cell Calcium. 16: 239–246.
Nicotera, P., Zhivotovsky, B., and Orrenius, S. (1994) Nuclear calcium transport and the role of calcium in apoptosis. Cell Calcium 16: 279–288.
Kruman, I. I. and Mattson, M. P. (1999) Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J. Neurochem. 72: 529–540.
Sheu, S. S. and Jou, M. J. (1994) Mirochondrial free Ca2??concentration in living cells. J. Bioenerg. Biomembr. 26: 487–493.
Jou, M. J. and Sheu, S. S. (1992) Mitochondrial regulation of cytosolic Ca2??in cultured neonatal rat ventricular mytocytes. Biophys. J. 61: 164.
Jiang, S., Chow, S. C., Nicotera, P., and Orrenius, S. (1994) Intracellular Ca2??signals activate apoptosis in thymocytes: Studies using the Ca2?-ATPase inhibitor thapsigargin. Exp. Cell. Res. 212: 84–92.
Martens, J. S., Lougheed, M., Gomez-Munoz, A., and Steinbrecher, U. P. (1999) A modification of apolipoprotein B accounts for most of the induction of macrophage growth by oxidized low density lipoprotein. J. Biol. Chem. 274: 10903–10910.
Nicotera, P. and Orrenius, S. (1998) The role of calcium in apoptosis. Cell Calcium 23: 173–180.
Escargueil-Blanc, I., Salvayre, R., and Negre-Salvayre, A. (1994) Necrosis and apoptosis induced by oxidized low density lipoproteins occur through two calcium-dependent pathways in lymphoblastoid cells. FASEB J. 8: 1075–1080.
Matsumura, T. et al. (1997) Two intracellular signaling pathways for activation of protein kinase C are involved in oxidized low-density lipoprotein-induced macrophage growth. Arterioscler. Thromb. Vasc. Biol. 17: 3013–3020.
Borutaite, V., Morkuniene, R., and Brown, G. C. (1999) Release of cytochrome c from heart mitochondria is induced by high Ca2??and peroxynitrite and is responsible for Ca2?-induced inhibition of substrate oxidation. Biocheim. Biophys. Acta 1453: 41–48.
Perez-Terzic, C., Pyle, J., Jaconi, M., Stehno-Bittel, L., and Clapham, D. E. (1996) Conformational states of the nuclear pore complex induced by depletion of nuclear Ca2??stores. Science 273: 1875–1877.
Perez-Terzic, C., Stehno-Bittel, L., and Clapham, D. E. (1997) Nucleoplasmic and cytoplasmic differences in the fluorescence properties of the calcium indicator Fluo-3. Cell Calcium 21: 275–282.
Stehno-Bittel, L., Luckoff, A., and Clapham, D. E. (1995) Calcium release from the nucleus by InsP3 receptor channels. Neuron. 14: 163–167.
Bolsover, S. R., Kater, S. B., and Guthrie, P. B. (1996) Spatial gradients of cytosolic calcium concentration in neurones during paradoxical activation by calcium. Cell Calcium. 20: 373–379.
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Yang, X., Zhang, Y., Huang, Y. et al. Variations in Transmembrane Ca2+ Gradient and Apoptosis of Macrophages Induced by Oxidized Low Density Lipoprotein. Biosci Rep 21, 667–681 (2001). https://doi.org/10.1023/A:1014725127189
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DOI: https://doi.org/10.1023/A:1014725127189