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

doi:10.1016/S0021-9150(00)00526-8

Atherosclerosis

Volume 155, Issue 1, March 2001, Pages 37-44

https://doi.org/10.1016/S0021-9150(00)00526-8 Get rights and content

Abstract

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 μM (143% of the control) and 5-HT at 50 μM (211%). When added together, low concentrations of HNE (0.1 μM) and 5-HT (5 μM) 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 μg/ml) and pertussis toxin (10 ng/ml) inhibited the mitogenic effect of 5-HT only. Protein tyrosine kinase inhibitor erbstatin A (10 μM) 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 μM) 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 μg/ml) and antioxidants N-acetylcysteine (400 μM), vitamin C (200 μM), or vitamin E (20 μM). 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.

Introduction

Vascular smooth muscle cell (VSMC) growth is an important component in the initiation and progression of atherosclerosis and restenosis after angioplasty. Currently, after angioplasty, restenosis of coronary and to a lesser extent peripheral arteries remains a major clinical problem. Hypothetical mechanisms of restenosis after balloon dilation include activation and release of platelet growth factors, intimal migration and proliferation of VSMCs induced by growth factors and the multiple effects of oxidatively modified low-density lipoproteins (Ox-LDL) [1]. Recent findings suggest that Ox-LDL may play a key role in the atherosclerotic process [2]. Immunohistochemistry studies suggest that Ox-LDL accumulates in atherosclerotic lesions [3], [4]. Ox-LDL is characterized by altered chemical and physical properties, including elevated levels of lipid hydroperoxides, oxidized sterols, lysophosphatidylcholine, degradation fragments of apo B-100, and increased electrophoretic mobility [5]. It has also been demonstrated that reactive oxygen species, lysophosphatidylcholine, and oxidized lipids stimulate VSMC growth [6], [7], [8], [9], [10], [11]. 4-Hydroxy-2-nonenal (HNE) is a major product of lipid peroxidation that is produced by β-scission of alkoxyl radicals in polyunsaturated fatty acids such as arachidonic, linoleic, and linolenic acids that are present in LDL [12]. Several observations support the hypothesis that HNE may provide a link between oxidant generation, lipid peroxidation, and VSMCs proliferation in atherogenesis. HNE is a component of oxidized LDL and is found in atherosclerotic lesions [13]. Immunoreactive HNE is present at all stages of human atherosclerotic plaque but not in normal human arteries [14], and has also been identified in the neointima of balloon-injured baboon arteries [15]. Lipid peroxidation products, specifically HNE, have been found to stimulate chemotaxis of neutrophilis and growth of HeLa cell in other systems [16], [17], [18].

Serotonin (5-hydroxytryptamine, 5-HT), a major non-peptidergic substance released from activated platelets, mediates vasoconstriction and induces activation of other platelets. This contributes to the progression of coronary artery events by initiating thrombotic complications [18], [19], [20], [21], [22]. Our previous study showed that 5-HT is a mitogen for VSMCs, which may contribute to the progression of atherosclerotic lesion or neointimal proliferation after angioplasty [23], and has a synergistic interaction with mildly Ox-LDL on VSMCs proliferation when compared with native LDL [24].

The aim of the present study was to examine whether or not HNE, a component of oxidatively modified lipids, has a mitogenic effect on VSMCs and whether it can interact with 5-HT in inducing VSMCs proliferation.

Section snippets

Materials

HNE, 5-HT creatinine sulfate, N-acetylcysteine (NAC), l-ascorbic acid (vitamin C), pertussis toxin (PTX), bovine serum albumin (BSA), insulin, transferrin, pargyline, and trypsin-ethylenediamine tetraacetic acid (EDTA) were purchased from Sigma (St Louis, MO). d-α-Tocopherol (vitamin E) was obtained from Merck Co (West Point, PA), and erbastatin analog (erbstatin A) and Ro 31-8220 were from Calbiochem-Novabiochem Co (La Jolla, CA). LY 281067 was a gift from Eli Lilly Laboratories (Indianapolis,

Effect of HNE on VSMCs DNA synthesis

The concentration-dependent effect of HNE on [³H]thymidine incorporation into VSMCs DNA is shown in Fig. 1. HNE significantly increased [³H]thymidine incorporation in a concentration-dependent manner between 0.01 and 1 μM, with a maximal effect at a concentration of 1 μM (143±8%, P<0.005 vs. the control value). When VSMCs were incubated with higher concentration of HNE (>1 μM), there was a decrease in the [³H]thymidine incorporated, indicating that higher concentrations of HNE may be cytotoxic.

Effect of HNE with 5-HT on VSMCs DNA synthesis

Discussion

It is generally accepted that Ox-LDL plays an important role in the development of atherosclerosis by inducing VSMCs proliferation [28], [29]. HNE is a major product of lipid peroxidation and is known to be formed during the oxidation of LDL. In the present study, we show that HNE stimulates VSMCs proliferation in a concentration-dependent manner and acts synergistically with 5-HT in inducing VSMCs proliferation. LY 281067, a 5-HT₂ receptor antagonist, and PTX abolished the mitogenic effect of

Acknowledgements

This work was supported by the National Institute of Health/National Heart, Lung and Blood Institute Grant, RO1-HL39916, ROI-HL50653 and American Heart Association Grant-In-Aid (to C.R. Benedict). Presented in part at the American College of Cardiology 49th Annual Scientific Session, March 12–15, 2000, Anaheim, CA, USA.

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

Abstract

Introduction

Section snippets

Materials

Effect of HNE on VSMCs DNA synthesis

Effect of HNE with 5-HT on VSMCs DNA synthesis

Discussion

Acknowledgements

Prog. Cardiovasc. Dis.

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

Mol. Aspects Med.

J. Am. Coll. Cardiol.

Atherosclerosis

J. Am. Coll. Cardiol.

Atherosclerosis

Crit. Rev. Oncol. Hematol.

Free Radic. Biol. Med.

J. Lipid Med.

Biochem. Biophys. Acta

Biochem. Biophys. Acta

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Atherosclerosis

Lancet

Oxidative modification of LDL and atherogenesis

Circulation

Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man

J. Clin. Invest.

Distribution of oxidation-specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits

Arteriosclerosis

Biochemical, structural and functional properties of oxidized low density lipoprotein

Chem. Res. Toxicol.

Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression

Circ. Res.

Active oxygen species and lysophosphatidylcholine are involved in oxidized low density lipoprotein activation of smooth muscle cell DNA synthesis

Arterioscler. Thromb. Vasc. Biol.

Linoleic acid and its metabolites, hydroperoxyoctadecadienoic acids, stimulate c-fos, c-jun, and c-myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells

J. Clin. Invest.

Lysophosphatidylcholine and hydrogen peroxide act synergistically in inducing vascular smooth muscle cells proliferation (Abstract)

Circulation

Low density lipoprotein undergoes oxidative modification in vivo

Proc. Natl. Acad. Sci. USA

Immunostaining of human autopsy aortas with antibodies to modified apolipoprotein B and apoprotein (a)

Arterioscler. Thromb.

Induction of vascular endothelial growth factor in balloon-injured baboon arteries

Circ. Res.