Oxidized Low-Density Lipoproteins Potentiate the Mitogenic Effect of 5-Hydroxytryptamine on Vascular Smooth Muscle Cells
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概要
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Considerable attention has been focused on both highly oxidized low-density lipoprotein (ox-LDL) and mildly oxidized LDL (mox-LDL) as important risk factors for cardiovascular disease. Further, 5-hydroxytryptamine (5-HT) appears to play a crucial role in the development of atherosclerotic plaque. We assessed the interaction of oxidatively modified LDL and its major oxidative components, ie, hydrogen peroxide (H2O 2), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) with 5-HT on DNA synthesis in vascular smooth muscle cells (VSMCs). Growth-arrested rabbit VSMCs were incubated in serum-free medium with native LDL, mox-LDL, ox-LDL (all 50 ng/mL), H2O2 (0.5 μM), LPC (1 μM), or HNE (0.1 μM) for 24 hours followed by 5-HT (5 μM) for another 24 hours. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. Significant effects on [3H]thymidine incorporation were observed in VSMCs incubated with mox-LDL (129%), ox-LDL (129%), H2O2 (119%), LPC (115%), HNE (127%), or 5-HT (183%) in contrast with native LDL (113%). The mitogenic effect of 5-HT was potentiated by mox-LDL, ox-LDL, H2O2, LPC, or HNE (183 to 365%, 274%, 304%, 339%, or 273%, respectively) but not by native LDL (240%). The mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 (10 μM) signficantly inhibited the mitogenic effect of 5-HT but did not influence the effects of mox-LDL, ox-LDL, H2O2, LPC, or HNE. The intracellular antioxidant N-acetylcysteine (400 μM) siginificantly inhibited the mitogenic effects of mox-LDL, ox-LDL, H2O2, LPC, and HNE but not that of 5-HT. Our results suggest that mox-LDL, ox-LDL, and their major components H2O 2, LPC, and HNE act synergistically with 5-HT in inducing VSMC DNA synthesis via MAPK and redox-sensitive pathways, contributing to the development of atherosclerotic plaque.
著者
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Katagiri Takashi
The Third Department of Internal Medicine, Showa University school of Medicine
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Benedict Claude
Department Of Internal Medicine University Of Texas-houston Health Science Center
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Watanabe Takuya
The Third Department of Internal Medicine
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Pakala Rajbabu
Department of Internal Medicine, Division of Cardiology, Univeristy of Texas-Houston Health Science
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Katagiri Takashi
The Third Department Of Internal Medicine Showa University
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Pakala Rajbabu
Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Health Science Center
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