Fatty acid and phospholipid chlorohydrins cause cell stress and endothelial adhesion
Languages of publication
The oxidation of low-density lipoprotein (LDL) is thought to contribute to atherogenesis, which is an inflammatory disease involving activation of phagocytic cells. Myeloperoxidase, an enzyme which is able to produce hypochlorous acid (HOCl), is released from these phagocytic cells, and has been found in an active form in atherosclerotic plaques. HOCl can oxidize both the lipid and protein moiety of LDL, and HOCl-modified LDL has been found to be pro-inflammatory, although it is not known which component is responsible for this effect. As HOCl can oxidize lipids to give chlorohydrins, we hypothesized that phospholipid chlorohydrins might have toxic and pro-inflammatory effects. We have formed chlorohydrins from fatty acids (oleic, linoleic and arachidonic acids) and from phospholipids (stearoyl-oleoyl phosphatidylcholine, stearoyl-linoleoyl phosphatidylcholine and stearoyl-arachidonoyl phosphatidylcholine), and investigated various biological effects of these oxidation products. Fatty acid and phospholipid chlorohydrins were found to deplete ATP levels in U937 cells in a concentration-dependent manner, with significant effects observed at concentrations of 25 µM and above. Low concentrations (25 µM) of stearoyl-oleoyl phosphatidylcholine and stearoyl-arachidonoyl phosphatidylcholine chlorohydrins were also found to increase caspase-3 activity. Finally, stearoyl-oleoyl phosphatidylcholine chlorohydrin increased leukocyte adhesion to artery segments isolated from C57Bl/6 mice. These results demonstrate potentially harmful effects of lipid chlorohydrins, and suggest that they may contribute to some of the pro-inflammatory effects that HOCl-modified low density lipoprotein has been found to induce.
- Bergt C, Pennathur S, Fu X, Byun J, O'Brien K, McDonanld TO, Singh P, Anantharamaiah GM, Chait A, Brunzell J, Geary RL, Oram JF, Heinecke JW (2004) The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA-1-dependent cholesterol transport. Proc Natl Acad Sci USA 101: 13032-13037.
- Brennan ML, Hazen SL (2003) Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment. Curr Opin Lipidol 14: 353-359.
- Buttke TM, Sandstrom PA (1994) Oxidative stress as a mediator of apoptosis. Immunol Today 15: 7-10.
- Carr AC, Vissers MC, Domigan NM, Winterbourn CC (1997) Modification of red cell membrane lipids by hypochlorous acid and haemolysis by preformed lipid chlorohydrins. Redox Rep 3: 263-271.
- Chisolm GM, Steinberg D (2000) The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med 28: 1815-1826.
- Daugherty A, Rateri DL, Dunn JL, Heinecke JW (1994) Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 94: 437-444.
- Dever G, Stewart LJ, Pitt AR, Spickett CM (2003) Phospholipid chlorohydrins cause ATP depletion and toxicity to human myeloid cells. FEBS Lett 540: 245-250.
- Dever G, Spickett CM, Kennedy S, Rush C, Tennant G, Monopoli A, Wainwright CL (2006) The NO-donating pravastatin derivative (NCX 6550) reduces splenocyte adhesion and ROS generation in normal and atherosclerotic mice. J Pharmacol Exp Ther 320: 419-26.
- Hazell LJ, Arnold L, Flowers D, Waeg G, Malle E, Stocker R (1996) Presence of hypochlorite-modified proteins in human atherosclerotic lesions. J Clin Invest 97: 1535-1544.
- Hazen SL, Heinecke JW (1997) 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalysed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest 99: 2075-2081.
- Iwase H, Yamada Y, Uemura H, Nakaya H, Takatori T, Nagao M, Iwadate K (1997) Effect of monochlorohydrins of linoleic acid on guinea-pig cardiac papillary muscles. Biochem Biophys Res Comm 231: 295-298.
- Jerlich A, Pitt AR, Schaur RJ, Spickett CM (2000) Pathways of phospholipid oxidation by HOCl in human LDL detected by LC-MS. Free Radic Biol Med 28: 673-682.
- Katrantzis M, Baker M, Handley CJ, Lowther DA (1991) The oxidant hypochlorite (OCl->), a product of the myeloperoxidase system, degrades articular cartilage proteoglycan aggregate. Free Radic Biol Med 10: 101-109.
- Kopprasch S, Leonhardt W, Pietzsch J, Kuhne H (1998) Hypochlorite-modified low-density lipoprotein stimulates human polymorphonuclear leukocytes for enhanced production of reactive oxygen metabolites, enzyme secretion, and adhesion to endothelial cells. Atherosclerosis 136: 315-324.
- Kopprasch S, Pietzsch J, Westendorf T, Kruse HJ, Grassler J (2004) The pivotal role of scavenger receptor CD36 and phagocyte-derived oxidants in oxidized low density lipoprotein-induced adhesion to endothelial cells. Int J Biochem Cell Biol 36: 460-471.
- Lim SY, Tennant GM, Kennedy S, Wainwright CL, Kane KA (2006) Activation of mouse protease-activated receptor-2 induces lymphocyte adhesion and reactive oxygen species generation. Br J Pharmacol 149: 591-599.
- Madamanchi N, Vendrov A, Runge M (2005) Oxidative stress and cardiovascular disease. Arterioscler Thromb Vasc Biol 25: 29-38.
- Nguyen-Khoa T, Massy ZA, Witko-Sarsat V, Canteloup S, Kebede M, Lacour B, Drueke T, Descamps-Latscha B (1999) Oxidised LDL induces macrophage respiratory burst via its protein moiety: a novel pathway in atherogenesis? Biochem Biophys Res Commun 263: 804-809.
- Panasenko OM, Spalteholz H, Schiller J, Arnhold J (2003) Myeloperoxidase-induced formation of chlorohydrins and lysophospholipids from unsaturated phosphatidylcholines. Free Radic Biol Med 34: 553-562.
- Podrez EA, Abu-Soud HM, Hazen SL (2000) Myeloperoxidase-generated oxidants and atherosclerosis. Free Radic Biol Med 28: 1717-1725.
- Ross R (1993) The pathogenesis of atherosclerosis: an update: a perspective for the 90's. Nature 362: 801-809.
- Spickett CM, Dever G (2005) Studies of phospholipid oxidation by electrospray mass spectrometry: from analysis in cells to biological effects. Biofactors 24: 17-31.
- Subbanagounder G, Wong JW, Lee H, Faull KF, Miller E, Witztum JL, Berliner JA (2002a) Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. J Biol Chem 277: 7271-7281.
- Subbanagounder G, Deng Y, Borromeo C, Dooley AN, Berliner JA, Salomon RG (2002b) Hydroxy alkenal phospholipids regulate inflammatory functions of endothelial cells. Vascul Pharmacol 38: 201-209.
- Thukkani AK, McHowat J, Hsu F-F, Brennan M-L, Hazen SL, Ford DA (2003) Identification of α-chloro fatty aldehydes and unsaturated lysophosphatidylcholine molecular species in human atherosclerotic lesions. Circulation 108: 3128-3133.
- Vayssier M, Banzet N, Francois D, Bellmann K, Polla BS (1998) Tobacco smoke induces both apoptosis and necrosis in mammalian cells: differential effects of HSP70. Am J Physiol 275: L771-779.
- Vissers MC, Pullar JM, Hampton MB (1999) Hypochlorous acid causes caspase activation and apoptosis or growth arrest in human endothelial cells. Biochem J 344: 443-449.
- Vissers MCM, Carr AC, Winterbourn CC (2001) Fatty acid chlorohydrins and bromohydrins are cytotoxic to human endothelial cells. Redox Report 6: 49-55.
- Watson AD, Leitinger N, Navab M, Faull KF, Hörkkö S, Witztum JL, Palinski W, Schwenke D, Salomon RG, Sha W, Subbanagounder G, Fogelman AM, Berliner JA (1997) Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J Biol Chem 272: 13597-13607.
- Winterbourn CC, van den Berg JJM, Roitman E, Kuypers FA (1992) Chlorohydrin formation from unsaturated fatty acids reacted with hypochlorous acid. Arch Biochem Biophys 296: 547-555.
- Witztum JL, Steinberg D (1991) Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 88: 1785-1792.
- Woenckhaus C, Kaufmann A, Bussfeld D, Gemsa D, Sprenger H, Groene H-J (1998) Hypochlorite-modified LDL: chemotactic potential and chemokine induction in human monocytes. Clin Immunol Immunopathol 86: 27-33.
Publication order reference