Low Wall Shear Stress Promotes Atheroma via Arterial Iron Accumulation

Background: Low wall shear stress (WSS) at arterial bifurcations and curves damages endothelial cells, promoting the development of atherosclerosis. Although the accumulation of iron in plaques has been observed, the mechanisms behind it and its effects are not fully understood.

Methods: Detect the iron content in different parts of the mouse partial carotid artery ligation model and the aorta. The chelating iron therapy was used to assess the impact of low WSS-induced iron accumulation and atherosclerosis in the arterial wall. In vitro experiments utilized human umbilical vein endothelial cells and an orbital-shaker model to simulate WSS. Mice with endothelial cell-specific knockout of IRP2 (iron regulatory protein 2) and deletion of apoE (Apolipoprotein e; apoE^-/-IRP2^iEcko) were constructed, as well as a human umbilical vein endothelial cell line with IRP2 knockdown.

Results: We investigated the iron accumulation induced by low WSS in carotid arteries. Hinokitiol, an iron chelator, was found to reduce this iron buildup and decrease the progression of atherosclerosis. Low WSS in the carotid arteries led to chronic iron accumulation, which altered the expression of iron metabolism-related proteins in endothelial cells, particularly IRP2. Knocking down IRP2 in endothelial cells resulted in an increase in the expression of inflammation-related proteins and a significant elevation in the expression of HIFs (hypoxia-inducible factors). apoE^-/-IRP2^iEcko mice exhibited an increased susceptibility to atherosclerosis. The use of HIF inhibitors, PX-478 and PT-2385, was able to suppress the exacerbation of atherosclerosis in apoE^-/- mice caused by the endothelial cell-specific knockout of IRP2.

Conclusions: Our results indicate that low WSS-induced endothelial cell iron metabolism abnormalities, by inducing arterial wall iron accumulation and abnormal expression of iron metabolism-related proteins, promote the occurrence and development of atherosclerosis. The use of iron chelators can alleviate the onset and progression of low WSS-induced atherosclerosis.

atherosclerosis; carotid stenosis; endothelial cells; oxidative stress; vascular system injuries.