EFFECT OF IRON OVERLOAD AND IRON-DEFICIENCY ON ATHEROSCLEROSIS IN THEHYPERCHOLESTEROLEMIC RABBIT

It has been suggested that iron plays an important role in the pathoge nesis of atherosclerosis, primarily by acting as a catalyst for the at herogenic modification of LDL. Although some epidemiological data sugg est that high stored iron levels are an independent risk factor for co ronary artery disease and that iron has been detected in both early an d advanced atherosclerotic lesions, the evidence is often contradictor y and inconclusive. We used the New Zealand White rabbit to investigat e the effects of iron overload (FeO) and iron deficiency (FeD) on athe rosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol fo r the last 6 weeks of the study. Iron and antioxidant status and chole sterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglo bin, serum iron, and transferrin saturation compared with controls. Co nversely, FeO significantly increased transferrin Fe saturation. FeO b ut not FeD decreased plasma cholesterol levels compared with control a nimals both before (P<.05) and after (P=.055) cholesterol feeding. Nei ther FeO nor FeD had a significant effect on the levels of antioxidant s and lipid peroxidation products in plasma and aortic tissue or on th e susceptibility of LDL to ex-vivo oxidation. FeO significantly decrea sed aortic arch lesion formation by 56% compared with controls (P<.05) , whereas FeD had no significant effect. These results indicate that i n this animal model, FeO decreases rather than increases atheroscleros is, likely because iron dextran exerts a hypocholesterolemic effect. O ur data do not support the hypotheses that elevation of Fe stores incr eases or that a reduction of Fe stores by phlebotomy decreases the ris k of coronary artery disease.