Iron Overload Augments the Development of Atherosclerotic Lesions in Rabbits

Abstract

Iron, a major oxidant in vivo, could be involved in atherosclerosis through the induction of the formation of oxidized LDL, a major atherogenic factor. This study was designed to test this hypothesis experimentally. Four groups of New Zealand White rabbits were included: iron-overloaded/hypercholesterolemic (group A, n = 8), iron-overloaded (group B, n = 6), hypercholesterolemic (group C, n = 6), and untreated (group D, n = 6). Iron overload was achieved by the intramuscular administration of 1.5 g of iron dextran divided in 30 doses. Hypercholesterolemia was produced by feeding rabbit chow enriched with 0.5% (wt/wt) cholesterol. Serum iron, ferritin, cholesterol, triglycerides, and lipoperoxides in serum were measured throughout the study. Lipoperoxides were measured at the end of the study in liver, aorta, and spleen homogenates. Aortas of groups A and C had multiple lesions; however, group A had greater lesional involvement than group C (P < .05). Lesions were not observed in rabbits fed normal chow (group D). As expected, serum iron and ferritin were above normal levels in groups A and B. Serum cholesterol increased in groups A and C. Lipoperoxides in liver and spleen homogenates of iron-overloaded rabbits were increased. Interestingly, iron deposits were seen by ultrastructural studies in the arterial walls of rabbits in groups A and B. Our study suggests that iron overload augments the formation of atherosclerotic lesions in hypercholesterolemic rabbits.

Metabolic syndrome, insulin resistance and the inflammation markers C-reactive protein and ferritin

“…However, it seems likely that increased ferritin reflects both the involvement of inflammation, as CRP does, and independent actions of excess iron. It is known that increased accumulation of iron affects insulin synthesis and secretion in the pancreas (Wilson et al, 2003) and interferes with the insulin-extracting capacity of the liver (Niederau et al, 1984), thereby leading to peripheral hyperinsulinaemia and impaired insulin secretion; that deposition of iron in muscle reduces glucose uptake because of muscle damage; (Merkel et al, 1988) and that iron accelerates atherosclerosis and damages endothelium in experimental models (Araujo et al, 1995;Lekakis et al, 1999) (catalytic iron converts relatively unreactive radical species such as H 2 O 2 into highly reactive species such as hydroxyl radical, and thereby favours oxidative attack on cell membranes and other cell components) (Oberley, 1988;Wolff, 1993;Andrews, 1999;Beard, 2001). Since insulin in turn stimulates cellular iron uptake by increasing the externalization of transferrin receptor, and may also stimulate the production of erythropoietin (Davis et al, 1986), a vicious circle leading to insulin resistance and diabetes may set in.…”

HFE gene mutations in coronary atherothrombotic disease

“…Since Sullivan (1) raised the hypothesis that iron overload could be a risk factor for CAD, many investigators have tested this possibility, but no definitive conclusion has been reached due to conflicting results (3,4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(23)(24)(25). Since the occurrence of HFE gene mutations associated with HH provides a valuable opportunity to test indirectly whether iron overload plays a role in atherosclerosis, the prevalence of these two mutations in patients with coronary atherothrombosis and in healthy controls was determined in the present study.…”

“…In addition, with the demonstration that iron catalyzes the synthesis of oxygen-reactive products (2), it has been also proposed that iron could play a role in LDL lipid peroxidation (3,4), an early step in atherogenesis (5). To support this hypothesis, it has been experimentally observed that iron overload contributes to atherogenesis in rabbits (6); however, other investigators demonstrated that, in the same animal model, iron overload causes a decrease in plasma cholesterol levels as well as in the formation of lesions in the aortic arch (7). Similarly, whereas some epidemiological studies (8)(9)(10)(11) have found a positive association between CAD and clinical markers of iron overload, other reports have found either a negative association (12) or none at all (13,14).…”

Aliskiren Protects against Hypercholesterolemia and Oxidative Stress on Isolated Aortae in Cholesterol-Fed Rats

“…Thiobarbituric Acid-Reactive Substance (TBARS) assay of aortic homogenates [21]: 20 μL aortic homogenate was added to 2 mL 40 mmol/L H 2 SO 4 (Merck), then 0.25 mL 10% wt/vol phosphotungstic acid (Sigma Chemical Co) was added and mixed. The mixture was centrifuged at 3000 rpm for 10 minutes, the supernatant was discarded, and the sediment was mixed with 1 mL 40 mmol/L H 2 SO 4 and 0.15 mL 10% wt/vol phosphotungstic acid.…”