Ferryl Hemoglobin and Heme Induce A1-Microglobulin in Hemorrhaged Atherosclerotic Lesions with Inhibitory Function against Hemoglobin and Lipid Oxidation

International Journal of Molecular Sciences

Bo Åkerström¹  Magnus Gram²  Zoltán Hendrik³  Attila Péter Gergely³  Lívia Beke⁴  Gábor Méhes⁴  Tamás Gáll⁵  Dávid Pethő⁵  Annamária Nagy⁵  József Balla⁵  Csaba Tóth⁶  György Balla⁷ 

[1] Department of Clinical Sciences Lund, Infection Medicine, Lund University, 22184 Lund, Sweden;Department of Clinical Sciences Lund, Pediatrics, Lund University, 22184 Lund, Sweden;Department of Forensic Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;Division of Vascular Surgery, Department of Surgery, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;ELKH-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, 4032 Debrecen, Hungary;

关键词: atherosclerosis;    hemorrhage;    α₁-microglobulin;    hemoglobin oxidation;    heme;    Ferryl Hemoglobin;   

DOI  :  10.3390/ijms22136668

来源: DOAJ

【 摘 要 】

Infiltration of red blood cells into atheromatous plaques and oxidation of hemoglobin (Hb) and lipoproteins are implicated in the pathogenesis of atherosclerosis. α₁-microglobulin (A1M) is a radical-scavenging and heme-binding protein. In this work, we examined the origin and role of A1M in human atherosclerotic lesions. Using immunohistochemistry, we observed a significant A1M immunoreactivity in atheromas and hemorrhaged plaques of carotid arteries in smooth muscle cells (SMCs) and macrophages. The most prominent expression was detected in macrophages of organized hemorrhage. To reveal a possible inducer of A1M expression in ruptured lesions, we exposed aortic endothelial cells (ECs), SMCs and macrophages to heme, Oxy- and FerrylHb. Both heme and FerrylHb, but not OxyHb, upregulated A1M mRNA expression in all cell types. Importantly, only FerrylHb induced A1M protein secretion in aortic ECs, SMCs and macrophages. To assess the possible function of A1M in ruptured lesions, we analyzed Hb oxidation and heme-catalyzed lipid peroxidation in the presence of A1M. We showed that recombinant A1M markedly inhibited Hb oxidation and heme-driven oxidative modification of low-density lipoproteins as well plaque lipids derived from atheromas. These results demonstrate the presence of A1M in atherosclerotic plaques and suggest its induction by heme and FerrylHb in the resident cells.

【 授权许可】

Unknown