HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels
Introduction
One of the early events in atherogenesis is the adherence of monocytes to endothelium followed by migration into the subendothelial space [1], [2]. This process is potentiated by different chemoattractants; among them, monocyte chemotactic protein-1 (MCP-1) is one of the most powerful. MCP-1 is expressed by macrophage and smooth muscle cells (SMC), as shown in human [3], [4], [5] and rabbit [3], [6] atherosclerotic lesions, and in the vessel wall of hypercholesterolemic primates [7]. Activity neutralization studies indicated that MCP-1 is a major monocyte chemotactic factor produced by endothelial cells [8] and SMC [9]. Furthermore, minimally modified LDL increased monocyte chemotactic activity in SMC and endothelial cells through an induction of MCP-1 [10]. Recently, it has been shown that mice with a targeted disruption of the ccr2 gene, which encodes the MCP-1 receptor, failed to recruit macrophages [11], and mice lacking this cc-chemokine are less susceptible to atherosclerosis [12]. These results strongly suggest a role for MCP-1 in the recruitment of monocytes into the vessel wall in the setting of inflammation and hyperlipidemia. Therefore, MCP-1 is a good candidate molecule to evidence whether a treatment aimed to prevent lesion development achieves its target.
Clinical results with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in cardiovascular disease prevention and treatment suggest that their beneficial effects cannot be solely related to systemic lipid lowering. In fact, cardiovascular episode reduction rates have a faster occurrence than plaque regression [13]. Statins have shown a broad spectrum of activities in vitro on macrophages and vascular cells such as: inhibition of cell proliferation [14], [15]; inhibition of esterified cholesterol accumulation [16]; upregulation of endothelial nitric oxide synthase (NOS III) [17] and reduction of matrix metalloproteinases secretion [18]. Recent studies suggest that statins may also produce vascular effects in vivo by mechanisms independent of their systemic lipid lowering effects [19]; among them, improvement of endothelial-dependent vasodilatation [20] and antithrombotic effects [21], [22].
Recently, it has been shown that atorvastatin can reduce MCP-1 expression in SMC and monocytes in culture [23] and in femoral lesions induced by endothelial damage and atherogenic diet in rabbits [24]. However, cytokine-inducible NOS (NOS II) expression was downregulated with atorvastatin and simvastatin in the aorta of rabbits with advanced lesions heavily infiltrated with macrophages and severe combined dyslipidemia induced by a cholesterol-rich diet [25]. NOS II expressed by macrophages [26] and SMC [27] has been associated with the atherogenic process by a mechanism related to the enhancing of the oxidative stress [28], [29]. It is our hypothesis that HMG-CoA reductase inhibitors may exert regulation of gene expression at a vascular level during the initial stages of atherosclerotic lesion development, independently of their lipid-lowering potential. In the present study, we analyze the effect of pravastatin and atorvastatin on vessel wall expression of MCP-1 and NOS II, in a diet-induced hyperlipidemic swine model. Our results suggest that statins can modulate MCP-1 expression during atherosclerotic lesion development independently of their systemic lipid lowering potential.
Section snippets
Study design
Yorkshire-Albino pigs (body weight at initiation: 17±4 kg) were fed a cholesterol-rich diet (2% cholesterol; 1% cholic acid; 20% beef tallow) for 8 weeks. The polyunsaturated/saturated (P/S) fatty acid ratio was reduced from 1.1 to 0.6 in the atherosclerotic diet [30]. This feeding regime produced mild atherosclerotic lesions, as measured by conventional histology. Animals (n=12) were divided into three groups: hyperlipidemic controls, hyperlipidemic treated with atorvastatin (3 mg/kg/day) and
Results
Compared with placebo, non-HDL-cholesterol levels were reduced by both statins but using the scheduled dose, this reduction reached significance only in the atorvastatin-treated group (Table 2).
Arterial lesion formation induced by hyperlipidemia was mild in abdominal and iliac arteries, while it was more prominent in coronary arteries. Under these conditions, statins decreased plaque formation, as we have previously reported [32]. Fig. 1 shows representative serial arterial sections from a
Discussion
MCP-1 is a glycoprotein involved in the chemotaxis of monocytes and SMC, which contributes to the development of atherosclerotic lesions [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. This study shows that HMG-CoA reductase inhibitors reduce MCP-1 expression in different arterial vascular beds of treated pigs fed with a hyperlipidemic diet. The effect produced by two statins (atorvastatin and pravastatin) was similar, independently of their systemic cholesterol-lowering efficacy.
We have
Acknowledgements
This study was supported by funds provided by FIS 98/0715, FIS 98/0641 and FIC-Catalana Occidente. José Alfon was a fellow of the Fundación Privada de Investigación Cardiovascular. We thank the technical help of Maya Garcı́a Zayas.
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Present address: J. Uriach & Cı́a; Degà Bahı́ 59; 08026 Barcelona, Spain.