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(Circulation. 2001;103:1440.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Lysophosphatidylcholine and Reactive Oxygen Species Mediate the Synergistic Effect of Mildly Oxidized LDL With Serotonin on Vascular Smooth Muscle Cell Proliferation

Takuya Watanabe, MD; Rajbabu Pakala, PhD; Shinji Koba, MD; Takashi Katagiri, MD; Claude R. Benedict, MD, DPhil

From the Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Health Science Center (T.W., R.P., C.R.B.), and Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan (S.K., T.K.).

Correspondence to Claude R. Benedict, MD, DPhil, Department of Internal Medicine, Division of Cardiology, The University of Texas-Houston Health Science Center, 6431 Fannin, MSB 6.039, Houston, TX 77030. E-mail c.benedic{at}heart.med.uth.tmc.edu

Background—Mild oxidation of LDL enhances its atherogenic potential and induces a synergistic interaction with serotonin (5HT) on vascular smooth muscle cell (VSMC) proliferation. Because of its complex chemical nature, the mitogenic components of mildly oxidized LDL (moxLDL) remain unclear.

Methods and Results—We examined both the effects of lysophosphatidylcholine (LPC) and hydrogen peroxide (H₂O₂), a donor of reactive oxygen species, as major components of moxLDL and their interactions with 5HT on VSMC proliferation. Growth-arrested VSMCs were incubated with different concentrations of moxLDL, LPC, H₂O₂, or LPC with H₂O₂ in the absence or presence of 5HT. DNA synthesis in VSMCs was examined by [³H]thymidine incorporation. MoxLDL, LPC, H₂O₂, and 5HT stimulated DNA synthesis in a dose-dependent manner. MoxLDL had a maximal stimulatory effect at a concentration of 5 µg/mL (211%), LPC at 15 µmol/L (156%), H₂O₂ at 5 µmol/L (179%), and 5HT at 50 µmol/L (205%). Added together, moxLDL (50 ng/mL) and 5HT (50 µmol/L) synergistically increased DNA synthesis (443%). Coincubation of LPC (1 µmol/L) with H₂O₂ (0.5 µmol/L) and 5HT (5 µmol/L) resulted in a synergistic increase in DNA synthesis (439%), which was nearly equal to that of moxLDL with 5HT (443%). The combined effects of LPC, H₂O₂, and 5HT on DNA synthesis were completely reversed by the combined use of an antioxidant, N-acetylcysteine (400 µmol/L) or butylated hydroxytoluene (20 µmol/L), with a 5HT₂ receptor antagonist, LY281067 (10 µg/mL).

Conclusions—Our results suggest that both LPC and reactive oxygen species may contribute to the mitogenic effect of moxLDL on VSMCs and its synergistic effect with 5HT.

Key Words: antioxidants • atherosclerosis • lipoproteins • muscle, smooth • platelet-derived factors

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