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

Q1 · MEDICINE

Article

Author: Koba, Shinji ; Benedict, Claude R. ; Pakala, Rajbabu ; Watanabe, Takuya ; Katagiri, Takashi

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 (H 2 O 2 ), 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, H 2 O 2 , or LPC with H 2 O 2 in the absence or presence of 5HT. DNA synthesis in VSMCs was examined by [ 3 H]thymidine incorporation. MoxLDL, LPC, H 2 O 2 , 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%), H 2 O 2 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 H 2 O 2 (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, H 2 O 2 , 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 5HT 2 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.

01 Mar 2001·AtherosclerosisQ2 · MEDICINE

Lipid peroxidation product 4-hydroxy-2-nonenal acts synergistically with serotonin in inducing vascular smooth muscle cell proliferation

Q2 · MEDICINE

Article

Author: Takuya Watanabe ; Claude R. Benedict ; Rajbabu Pakala ; Takashi Katagiri

Formation of an atherosclerotic lesion is in part mediated by inflammatory and oxidative mechanisms including lipid peroxidation. To characterize the potential role of lipid peroxidation products in atherogenesis, we assessed the effect of 4-hydroxy-2-nonenal (HNE), a component of oxidatively modified lipids on vascular smooth muscle cells (VSMCs) proliferation, and its interaction with serotonin (5-hydroxytryptamine, 5-HT), a known mitogen for VSMCs. Growth-arrested rabbit VSMCs were incubated with different concentrations of HNE in the absence or presence of 5-HT. VSMCs proliferation was examined by increases in [3H]thymidine incorporation into DNA and cell number. HNE and 5-HT stimulated DNA synthesis in a dose-dependent manner. HNE had a maximal proliferative effect at a concentration of 1 microM (143% of the control) and 5-HT at 50 microM (211%). When added together, low concentrations of HNE (0.1 microM) and 5-HT (5 microM) synergistically induced DNA synthesis (273%). These effects on DNA synthesis were paralleled by an increase in cell number. A 5-HT2 receptor antagonist LY 281067 (10 microg/ml) and pertussis toxin (10 ng/ml) inhibited the mitogenic effect of 5-HT only. Protein tyrosine kinase inhibitor erbstatin A (10 microM) completely inhibited the mitogenic effect of HNE and partially that of 5-HT and the combined effect of HNE+5-HT. Protein kinase C inhibitor Ro 31-8220 (0.1 microM) completely inhibited mitogenic effects of both HNE and 5-HT, and also the combined effect of HNE+5-HT. The synergistic effect of HNE+5-HT on DNA synthesis was completely reversed by the combined use of LY 281067 (10 microg/ml) and antioxidants N-acetylcysteine (400 microM), vitamin C (200 microM), or vitamin E (20 microM). Our results suggest that HNE acts synergistically with 5-HT in inducing VSMCs proliferation. Combined use of both antiplatelet and antioxidant therapies may be useful for the prevention of VSMCs proliferative disorders associated with atherosclerosis and restenosis after angioplasty.

01 Dec 1999·Journal of Laboratory and Clinical Medicine

Synergy between thrombin and serotonin in inducing vascular smooth muscle cell proliferation

Article

Author: Claude Benedict ; Rajbabu Pakala

Previous studies have indicated that apart from playing an important role in hemostasis and thrombosis, thrombin may also contribute to the development of postangioplasty restenosis caused by the stimulation of vascular smooth muscle cell (VSMC) proliferation. Because thrombin generation in vivo is accompanied by platelet activation and release of smooth muscle cell (SMC) growth factors such as serotonin, we examined the possible interaction between these two compounds on VSMC proliferation. Thrombin (0.01 to 100 nmol/L), thrombin receptor-activating peptide (0.1 to 1000 micromol/L), and serotonin (5HT; 0.1 to 1000 micromol/L) increased tritiated thymidine incorporation into the DNA of canine aortic VSMCs in a dose-dependent manner. When thrombin and 5HT were added together at sub-threshold concentrations, they acted synergistically in inducing tritiated thymidine incorporation. These findings were paralleled by a 90%+/-5% increase in the cell number at 48 hours, as compared with a 37%+/-2% increase with 50 micromol/L serotonin and a 13%+/-3% increase with 0.1 nmol/L thrombin. We also demonstrated that a brief exposure to thrombin (1 hour) is sufficient to show its potentiating effect on serotonin. The mitogenic effect of serotonin and its synergistic interaction with thrombin on VSMC proliferation was abolished by serotonin type 2 receptor antagonist LY281067. Similarly, gamma-hirudin--a direct thrombin inhibitor--blocked the mitogenic effect of thrombin and its synergistic interaction with serotonin. When LY281067 and gamma-hirudin were used together, they abolished the mitogenic effects of both the agonists. Because clot-bound active thrombin can escape inactivation by anti-thrombin, this thrombin may potentiate the mitogenic effect of serotonin and keep the SMCs in a proliferative state for a long period of time. These findings support the use of 5HT2 receptor antagonists in combination with thrombin inhibitors in the prevention of SMC proliferation after coronary angioplasty.

100 Deals associated with Sergolexole Maleate

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