Probucol and ticlopidine: effect on platelet and monocyte activation markers in hyperlipidemic patients with and without type 2 diabetes

Abstract

We investigated the effects of probucol and ticlopidine on circulating levels of platelet activation markers, microparticles, soluble selectins, and malondialdehyde-low density lipoprotein (MDA-LDL) in hyperlipidemic patients with or without type 2 diabetes. There were significant differences in the levels of CD62P, PAC-1, annexin V, PDMP, MDMP, sP-selectin, sE-selectin and MDA-LDL between the hyperlipidemic patients and the controls. In particular, these markers were significantly increased in hyperlipidemic patients who had type 2 diabetes. In the hyperlipidemic patients with diabetes, MDA-LDL was decreased by both monotherapy with probucol and combination therapy (probucol and ticlopidine). In these patients, CD62P, PAC-1, annexin V, MDMP, PDMP, sP-selectin, and sE-selectin were also significantly decreased after treatment. The decreases of CD62P, PAC-1, annexin V, PDMP and sP-selectin were greater combination therapy than with monotherapy. These findings suggest that administration of probucol and ticlopidine to hyperlipidemic patients with type 2 diabetes may help to prevent the development of cardiovascular complications caused by modified LDL, selectins, or activated platelets and monocytes.

Introduction

In patients with type 2 diabetes mellitus, the prevalence of hyperlipidemia, hypertension, and obesity is increased, resulting in increase of cardiovascular complications [1], [2], [3]. A high plasma cholesterol level has been clearly identified as a risk factor for atherosclerosis and cardiovascular disease [4]. In addition, a high plasma level of low-density lipoprotein (LDL) cholesterol may promote the development of atherosclerotic disease [5]. Because modified LDL can transfer cholesterol to macrophages but unmodified LDL cannot [6], it has been postulated that circulating LDL must first undergo postsecretory modification before taking part in the atherosclerotic process [7]. Several different mechanisms [8] may be involved in the modification of LDL in vivo, including auto-oxidation, and malondialdehyde (MDA) may have a role [9], [10].

Monocytes and macrophages have also been suggested to play an important role in the development of atherosclerosis [11], [12]. The first step in the process of monocyte infiltration into the subendothelial space is adhesion of circulating cells to the endothelium. Macrophages are the predominant cell type in the lipid core of atherosclerotic plaques [13], and have been shown to express tissue factor [14]. Monocytes can synthesize procoagulant substances, although this ability seems to be largely confined to tissue factor [15]. The release of heterogenous microparticles by endotoxin-stimulated monocytes has been suggested as a possible mechanism for regulating the functions of vascular cell [16]. These monocyte-derived microparticles (MDMP) promote the assembly of the prothrombinase complex, thus facilitating the intravascular generation of thrombin and enhancement of procoagulant activity [17], [18]. Similar actions have been ascribed to various markers of platelet activation, such as platelet CD62P (plt-CD62P) and platelet-derived microparticles (PDMP) [19], [20]. Thus LDL, monocytes, and platelets all have an important influence on vascular events.

Although avoiding the oxidative modification of lipoproteins is an important target for the prevention of atherosclerosis, the most effective method for reducing oxidative modification of LDL is unknown. Probucol is used clinically for the treatment of hypercholesterolemia, and this drug has been reported to prevent atherogenesis by acting as an antioxidant and suppressing the oxidative modification of LDL, in addition to its recognized cholesterol-lowering effect [21]. Furthermore, probucol inhibits the adhesion of monocytes to the vascular endothelium in cholesterol-fed rabbits [22], and has been shown to improve endothelium-dependent relaxation in hypercholesteloremic animals [23], [24].

The two objectives of the present study were: (1) to assess the role of monocyte activation markers, platelet activation markers, and modified LDL in vascular damage related to hyperlipidemia, and (2) to evaluate the efficacy of probucol and ticlopidine in preventing such vascular damage.