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

Dávid Pethő,Attila Péter Gergely,Lívia Beke,György Balla,Bo Åkerström,Magnus Gram,Tamás Gáll,József Balla,Annamária Nagy,Gábor Méhes,Zoltán Hendrik,Csaba Tóth

doi:10.3390/ijms22136668

Abstract

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.

Highlights

Hemeproteins play vital roles in oxygen and electron transports, as well as in oxidation–reduction enzyme reactions
Since Hb oxidation derivatives and free heme play an essential role in atherosclerotic plaque development, we suggest that heme-binding and antioxidant protein atherosclerosis. α1-microglobulin (A1M) might be involved in the protection of the arterial wall against Hb/heme-driven damage
To analyze the cellular distribution of A1M, smooth muscle cells were identified by smooth muscle α-actin (SMA), macrophages by CD68, while endothelial cells by CD34 staining

Summary

Introduction

Hemeproteins play vital roles in oxygen and electron transports, as well as in oxidation–reduction enzyme reactions. Hemeproteins play vital roles in oxygen and electron transports, as well as in oxidation–. Hemoglobin (Hb), responsible for oxygen transport, is the most abundant hemeprotein in humans. Hb oxidation is a common phenomenon in pathological states and in physiological conditions [1,2,3,4]. Hb undergoing a natural auto-oxidation in red blood cells (RBCs) generates reactive oxygen species (ROS) and hydrogen peroxide (H2 O2 ) [5,6,7]. In vascular pathological conditions, such as atherosclerosis with intraplaque hemorrhage [10], subarachnoid hemorrhage [11], sickle cell disease [12] and sepsis [13], Hb is liberated from RBCs and accumulates as cell-free Hb in tissues out of control from the cellular antioxidant defense system

Methods

Results

Conclusion