HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, 4012 Debrecen, Hungary.
Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4012 Debrecen, Hungary.
Int J Mol Sci. 2020 Jul 3;21(13):4746. doi: 10.3390/ijms21134746.
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.
血红蛋白、血红素和铁与动脉粥样硬化的进展有关。因此，我们研究了疏水性真菌铁螯合剂脱铁叶绿酸（DFC）是否能抑制动脉粥样硬化。DFC 可减少动脉粥样硬化病变的形成在载脂蛋白 E 基因敲除小鼠高脂饮食。它降低了氧化低密度脂蛋白（oxLDL）的血浆水平，并抑制了主动脉根部的脂质过氧化。胶原/弹性蛋白含量的升高和粘附分子 VCAM-1 的表达增强均降低。DFC 可减少血红蛋白或血红蛋白催化的低密度脂蛋白（LDL）和斑块脂质的氧化。DFC 减少泡沫细胞的形成，减少巨噬细胞对 oxLDL 的摄取，下调 CD36 的表达，并降低 TNF-α的表达。DFC 还能抑制 TNF-α触发的内皮细胞活化（血管细胞粘附分子-1（VCAM-1）、细胞间粘附分子（ICAMs）、E-选择素）和单核细胞与内皮的粘附增加。DFC 还可防止 TNF-α引起的内皮通透性增加和细胞内间隙形成。DFC 作为一种细胞保护剂，在受到致死剂量 oxLDL 挑战的内皮细胞和巨噬细胞中发挥作用，并降低应激反应血红素加氧酶-1的表达，而亚致死剂量则发挥作用。铁对脱铁叶绿酸的饱和导致其有益作用丧失。我们证明 DFC 在载脂蛋白 E 基因敲除小鼠的主动脉粥样斑块中积累。DFC 代表了一种控制动脉粥样硬化进展的新的治疗方法。
