Pathogenic mechanisms of ironinduced atherosclerosis

Atherosclerosis is a slow disease, starting in childhood, and progressing during ageing. It is due to a chronic inflammatory process coupled with dyslipidaemia. Two major mechanisms initiating the plaque formation include the oxidation of LDL-cholesterol and the transendothelial migration of leucocytes to the intima underneath the endothelial layer of the arterial vessels. Other processes involved in atherogenesis include T-cell and monocyte-mediated inflammation reactions, macrophage foam cell formation and proliferation of smooth muscle cells (Dzau et al. 2002). There are several possible mechanisms of iron involvement in atherosclerosis (Fig. 6.4)

Smooth muscle ceil " proliferation fontmlg fibrous cap

Smooth muscle ceil " proliferation fontmlg fibrous cap

Smooth muscle cells

Fig. 6.4 Illustration of the cellular process and possible action of iron in the development of atherosclerosis. Fe = iron. P-selectin = platelet selectin. E-selectin = endothelial selectin.VLA-4 = very late activation antigen-4. VCAM-1 = vascular cell adhesion molecule-1. LFA-1 = lymphocyte function-associated antigen-1. ICAM-1 = intercellular adhesion molecule-1. MCP-1 = monocyte chemoattractant protein-1. CCR-2 = CC chemokine receptor-2. M-CSF = macrophage colony-stimulating factor. TF = tissue factor. vWF = von Willebrand factor. MMP = matrix metalloproteinases. NO = mononitrogen oxide. ROS = reactive oxygen species. LDL = low-density lipoprotein. These cellular processes may include: rolling, adherence and transendothelial migration of leucocytes, macrophage and T-cell mediated inflammation reaction, LDL oxidation, foam cell formation, decreased NO production, smooth muscle cell proliferation and platelet aggregation.

In vitro studies

The mechanism by which iron may stimulate atherogenesis is unclear. It is suggested that the catalytic role of iron in lipid peroxidation may influence the formation of atherosclerotic lesions. Iron-catalysed free radical formation may cause oxidation of LDL (Heinecke et al. 1984). The oxidised LDL is recognised by scavenger-receptors on macrophages, leading to accumulation of LDL in the cells. This is followed by the formation of foam cells, which are characteristic for the fatty-streak lesions of early atherosclerosis. Oxidised LDL also has chemotactic capacity providing recruitment of monocytes and macrophages to the site of lesions. The oxidised LDL also has cytotoxic capacity that induces changes in the endothelial cells with loss of endothelial integrity.

Transendothelial migration of leucocytes is also a fundamental inflammatory mechanism in atherogenesis (Gerrity 1981, Ross 1999). This process is partly mediated by chemokines and the interaction between endothelial adhesion molecules and their ligands on monocytes (Meerschaert & Furie 1995; Navab et al. 1994; Shang & Issekutz 1998). Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes bearing the chemokine receptor CCR-2 (Springer 1994). Several adhesion molecules have been shown to be present in human atherosclerotic plaques, including two members of the immunoglobulin superfamily of adhesion receptors, ICAM-1 (O'Brien et al. 1996; Printseva et al. 1992; van der Wal et al. 1992), VCAM-1 (O'Brien et al. 1993; O'Brien et al. 1996), as well as a member of the selectin family, E-Selectin (O'Brien et al. 1996; van der Wal et al. 1992). A significant correlation has been found between the degree of macrophage infiltration and endothelial ICAM-1, VCAM-1 and E-selectin expression in atherosclerotic lesions (O'Brien et al. 1996).

As a redox active metal, iron is capable of catalysing the formation of hydroxyl radicals in the Fenton reaction (Marx & van Asbeck 1996). Several antioxidants have been shown to protect against the endothelial dysfunction associated with atherosclerosis (Diaz et al. 1997). The oxygen radicals may involve in the regulation of nuclear factor KB (NF-k/) DNA binding (Baldwin 2001), important for the transcription of a large number of genes, including the endothelial adhesion molecules (Collins et al. 1995; Neish et al. 1992).

The infiltration of leucocytes consists of consecutive adhesion-mediated events (Butcher 1991). The first step of adherence involves binding of selectins to carbohydrate ligands, which triggers tethering of the leucocytes to the activated endothelium along the vessel wall. After rolling and arrest, a firm adhesion of the leucocytes on activated endothelial cells may occur depending on the activation of the integrins including VLA-4 and LFA-1 (Adams & Shaw 1994; Luscinskas et al. 1994; Ross 1995; Springer 1994, 1995). Such activation may involve signalling initiated by inflammatory cytokines or signalling through binding of the integrins to their receptors (Adams & Lloyd 1997; Dedhar 1999; Ebnet et al. 1996; Ebnet & Vestweber 1999; Gahmberg 1997; Tuomainen et al. 1997a). Iron in vitro upregulates interleukin-6 (IL-6) production by endothelial cells (Visseren et al. 2002), while iron chelators inhibit the tumor necrosis factor-a (TNF-a mediated up regulation of endothelial adhesion molecules (Koo et al. 2003, Zhang & Frei 2003). Expression of IFN-K-inducible genes in monocytic cells was affected by iron and iron-chelation (Oexle et al. 2003). Moreover, iron was shown to increase secretion of TNF-a (Lopez et al. 2003) and IL-1 (Szkaradkiewicz 1991) by monocytes.

In vivo studies

The in vitro experimental studies on generation of oxidised LDL by iron are supported by observation of the atherosclerotic lesions. The interior of advanced human atherosclerotic lesions is a highly pro-oxidant environment containing redox-active iron and copper ions which may induce lipid peroxidation (Smith et al. 1992). Ferritin was also found to be highly expressed in the atherosclerotic lesions (Pang et al. 1996). The iron is colocalised with ceroid, an insoluble complex of oxidised lipid and protein, extracellularly and also intracellularly in the foam cells and smooth muscle cells (Lee et al. 1998). Iron deposits causing stimulation of macrophage infiltration to the atherosclerotic lesions and furthermore plaque rupture have recently been shown (Kolodgie et al. 2003). Further study by means of scanning and transmission electron microscopy revealed that erythrocytes containing haemoglobin were present in atherosclerotic lesions. Erythrophagocytosis by macrophages also occurred in the lesions (Lee et al. 1999a).

One study showed that patients with genetic haemochromatosis had significant eccentric hypertrophy of the radial artery, although none of them had arterial hypertension or evidence of cardiovascular diseases (Failla et al. 2000). The structural alteration leading to functional problems (stiffening), was largely reverted by iron depletion (Failla et al. 2000). Iron was also shown to induce early functional and structural vascular abnormalities due to endothelial dysfunction (Rooyakkers et al. 2002) which is associated with subsequent induction of oxidative stress. The radical species may also impair the mononitrogen oxide (NO) production, leading to the condition of arterial stiffness (Cheung et al. 2002). The vascular condition could be improved after administration of iron chelator (Duffy et al. 2001), which may indicate a reduced risk of cardiovascular events.

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