Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction

Abstract

Aims Whether and how iron affects the progression of atherosclerosis remains highly debated. Here, we investigate susceptibility to atherosclerosis in a mouse model (ApoE−/− FPNwt/C326S), which develops the disease in the context of elevated non-transferrin bound serum iron (NTBI). Methods and results Compared with normo-ferremic ApoE−/− mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE−/− FPNwt/C326S mice, suggesting a pro-atherogenic role for iron. Iron heavily deposits in the arterial media layer, which correlates with plaque formation, vascular oxidative stress and dysfunction. Atherosclerosis is exacerbated by iron-triggered lipid profile alterations, vascular permeabilization, sustained endothelial activation, elevated pro-atherogenic inflammatory mediators, and reduced nitric oxide availability. NTBI causes iron overload, induces reactive oxygen species production and apoptosis in cultured vascular cells, and stimulates massive MCP-1-mediated monocyte recruitment, well-established mechanisms contributing to atherosclerosis. NTBI-mediated toxicity is prevented by transferrin- or chelator-mediated iron scavenging. Consistently, a low-iron diet and iron chelation therapy strongly improved the course of the disease in ApoE−/− FPNwt/C326S mice. Our results are corroborated by analyses of serum samples of haemochromatosis patients, which show an inverse correlation between the degree of iron depletion and hallmarks of endothelial dysfunction and inflammation. Conclusion Our data demonstrate that NTBI-triggered iron overload aggravates atherosclerosis and unravel a causal link between NTBI and the progression of atherosclerotic lesions. Our findings support clinical applications of iron restriction in iron-loaded individuals to counteract iron-aggravated vascular dysfunction and atherosclerosis.

Transferrin plays a central role in coagulation balance by interacting with clotting factors

“…43 Iron overload can aggravate AS by inducing oxidative stress and inflammation according to a recent report. 44 Study has demonstrated that ferritin, the iron storage protein, is highly expressed in human atherosclerotic lesions. 45 It has been reported that transferrin receptor 1 and ferritin were highly expressed in foamy macrophages and smooth muscle cells in intimal lesions of human carotid atheroma, in association with the severity of plaques.…”

Iron Accumulation in Macrophages Promotes the Formation of Foam Cells and Development of Atherosclerosis

“…Considering the key roles of macrophages in the formation and progression of atherosclerotic plaques, combined with the fact that macrophages provide a large amount of iron in the circulation to meet systemic requirements by recycling iron from senescent red blood cells (11), selective iron deposition in macrophages has been proposed as a mechanism underlying accelerated atherosclerosis progression via catalytic generation of reactive oxygen species (ROS) and thus promotion of foam cell formation (12,13). Several mouse models of iron overload (i.e., high-iron diet or injection with iron-dextran (14,15) and hereditary hemochromatosis (HH) (16)(17)(18) characterized by systemic iron overload rather than macrophage-specific iron deposition are likely not suitable to integrate the current data for elucidating the impact of iron on atherosclerosis.…”

The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

“…In addition, disorders of iron metabolism participate also in the mechanisms of other diseases, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease [ 13 ]. Regarding the cardiovascular system, iron overload can cause impaired vascular function and aggravate the development of atherosclerosis, arrhythmias, and heart failure, as well as overall morbidity of patients [ 6 , 12 , 14 ].…”