The Fungal Iron Chelator Desferricoprogen Inhibits Atherosclerotic Plaque Formation.

László Potor,József Balla,Zsuzsa Szabó,Zsolt Combi,Hajnalka Hegedűs,Dezső Szikra,Ildikó Garai,Zsuzsa M Szigeti,Dávid Pethő,Tamás Gáll,János Kappelmayer,Katalin Éva Sikura,György Balla,István Pócsi,György Trencsényi

doi:10.3390/ijms21134746

Abstract

Hemoglobin, heme and iron are implicated in the progression of atherosclerosis. Therefore, we investigated whether the hydrophobic fungal iron chelator siderophore, desferricoprogen (DFC) inhibits atherosclerosis. DFC reduced atherosclerotic plaque formation in ApoE−/− mice on an atherogenic diet. It lowered the plasma level of oxidized LDL (oxLDL) and inhibited lipid peroxidation in aortic roots. The elevated collagen/elastin content and enhanced expression of adhesion molecule VCAM-1 were decreased. DFC diminished oxidation of Low-density Lipoprotein (LDL) and plaque lipids catalyzed by heme or hemoglobin. Formation of foam cells, uptake of oxLDL by macrophages, upregulation of CD36 and increased expression of TNF-α were reduced by DFC in macrophages. TNF-triggered endothelial cell activation (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules (ICAMs), E-selectin) and increased adhesion of monocytes to endothelium were attenuated. The increased endothelial permeability and intracellular gap formation provoked by TNF-α was also prevented by DFC. DFC acted as a cytoprotectant in endothelial cells and macrophages challenged with a lethal dose of oxLDL and lowered the expression of stress-responsive heme oxygenase-1 as sublethal dose was employed. Saturation of desferrisiderophore with iron led to the loss of the beneficial effects. We demonstrated that DFC accumulated within the atheromas of the aorta in ApoE−/− mice. DFC represents a novel therapeutic approach to control the progression of atherosclerosis.

Highlights

The pathomechanism of the atherosclerotic vascular disorders, which is the leading cause of death worldwide, is based on two main distinct concepts, the lipid and the inflammation theories
As previously described in ApoE−/− mice, the plasma high-density lipoprotein (HDL) cholesterol level decreased while the Low-density Lipoprotein (LDL) cholesterol level increased leading to the progression of atherosclerosis [53]
We showed that sublethal concentration of oxidized LDL (oxLDL) (50 μg/mL) provoked the expression of the stress-responsive protein heme oxygenase-1 (HO-1) in endothelial cells as well as in macrophages which were abrogated by DFC (50 μmol/L) in both cell types (Figure 4A,B)

Summary

Introduction

The pathomechanism of the atherosclerotic vascular disorders, which is the leading cause of death worldwide, is based on two main distinct concepts, the lipid and the inflammation theories. Lipids modification and oxidation are the initial steps of atherosclerosis, which provoke inflammation at the site of the artery wall [1]. There is a third approach, the lipid-inflammation synergy hypothesis since their signs can be observed parallel in atheromas [2]. The pathological deviation of plasma lipid profile is required to develop lipid plaques in most of the atherosclerotic cases, the oxidative modification of the Low-density Lipoprotein (LDL) is a necessary step to generate foam cells in the artery wall [3,4]. Previous studies suggest that smooth muscle cells contribute at least 50% of the origin of foam cells as compared to macrophages in human and mouse atheromas. The expression of smooth muscle cells markers, including smooth muscle cell α-actin and α-tropomyosin were decreased in smooth muscle cells during foam cell formation, while smooth muscle cells have become positive for macrophage markers, as well as CD68 and Mac-2 and transdifferentiated into endocytic phenotype [5,6]

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