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Red blood cell, hemoglobin and heme in the progression of atherosclerosis

SIGNIFICANCE STATEMENT

 

For decades plaque neovascularization was considered as an innocent feature of advanced atherosclerotic lesions, but nowadays growing evidence suggest that this process triggers plaque progression and vulnerability.  Neovascularization is induced mostly by hypoxia but the involvement of oxidative stress is also established. Deep and less-vascularized layers of human plaques are hypoxic and the hypoxia-inducible factor-1 pathway is activated leading to transcriptional up-regulation of target genes involved in adaptation to hypoxic condition. Such gene is vascular endothelial growth factor that has a pivotal role in angiogenesis. Plaque neovessels differ both anatomically and in their response to different stimuli from the normal vessels. Neovessels are dysmorphic and characterized by discontinuous basement membrane and a relatively low number of tight junctions between endothelial cells. Moreover these premature vessels are relatively poor in smooth muscle cells or pericytes. Consequently, neovessels are leaky and unable to control intraluminal pressure therefore they are prone to rupture. Continuous leakage or rupture of immature neovessels leads to extravasation of red blood cells (RBC) within plaques which process is defined as intraplaque hemorrhage (IPH). IPH is present in about 40% of high-risk plaques, and recently IPH has been linked to plaque progression and vulnerability and nowadays is considered as a critical event in triggering atherosclerosis-associated acute clinical symptoms. Alternatively, RBCs can enter the atheroma from the lumen of the artery. RBCs, in the highly oxidative environment of the atherosclerotic lesions, tend to lyse quickly. Both RBC membrane and the released hemoglobin (Hb) possess atherogenic activities. Cholesterol content of RBC membrane contributes to lipid deposition and lipid core expansion upon intraplaque hemorrhage. Hb once outside the protective environment of RBC is prone to oxidation leading to the formation of diverse oxidatively modified Hb species (oxHb) including metHb, ferrylHb, ferrylHb radical, metHb globin radical as well as globin-globin and globin-porphyrin crosslinked species. These oxHb species possess different pro-oxidant activities. OxHb and heme released from oxHb species are potent inducers of oxidative modification of low-density lipoprotein and plaque lipids. Furthermore heme and oxHb species provoke oxidative damage of vascular cells. Additionally, cell free Hb, oxHb species and heme possess specific immunomodulatory activities. OxHb is chemotactic, upregulates the expression of adhesion molecules in endothelial cells and increase the permeability of vascular endothelium. Cell free Hb and heme modulate macrophage polarization, leading to the formation of a recently identified hemorrhage-associated macrophage phenotype (Mhem, HA-mac) that is present in human hemorrhaged atherosclerotic plaques.
Figure Legend:Red blood cell in the death zone.

Hypoxic vascular smooth muscle cells trigger neovascularization of the atherosclertic lesion (1). Leakage or rupture of immature neovessels leads to extravasation of red blood cells (RBCs) within the plaques (2). Alternatively, RBCs can enter the atheroma from the lumen of the artery (3). RBC lysis occurs in the highly oxidative environment of the atherosclerotic lesions, leading to hemoglobin (Hb) release (4). Interactions between cell free Hb and plaque lipids (PL) lead to the formation of oxidatively modified Hb species (oxHb) (5). OxHb triggers and promotes oxidation of plaque lipids (oxPL) (6). OxPL enhances further lysis of RBCs (7) completing a vicious cycle.

Red blood cell, hemoglobin and heme in the progression of atherosclerosis. Global Medical Discovery

 

 

 

 

 

 

Jeney V1, Balla G2, Balla J3. Front Physiol. 2014 ;5:379.

1Department of Medicine, University of Debrecen Debrecen, Hungary ; MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences Debrecen, Hungary.

2MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences Debrecen, Hungary ; Department of Pediatrics, University of Debrecen Debrecen, Hungary.

3Department of Medicine, University of Debrecen Debrecen, Hungary.

Abstract

For decades plaque neovascularization was considered as an innocent feature of advanced atherosclerotic lesions, but nowadays growing evidence suggest that this process triggers plaque progression and vulnerability. Neovascularization is induced mostly by hypoxia, but the involvement of oxidative stress is also established. Because of inappropriate angiogenesis, neovessels are leaky and prone to rupture, leading to the extravasation of red blood cells (RBCs) within the plaque. RBCs, in the highly oxidative environment of the atherosclerotic lesions, tend to lyse quickly. Both RBC membrane and the released hemoglobin (Hb) possess atherogenic activities. Cholesterol content of RBC membrane contributes to lipid deposition and lipid core expansion upon intraplaque hemorrhage. Cell-free Hb is prone to oxidation, and the oxidation products possess pro-oxidant and pro-inflammatory activities. Defense and adaptation mechanisms evolved to cope with the deleterious effects of cell free Hb and heme. These rely on plasma proteins haptoglobin (Hp) and hemopexin (Hx) with the ability to scavenge and eliminate free Hb and heme form the circulation. The protective strategy is completed with the cellular heme oxygenase-1/ferritin system that becomes activated when Hp and Hx fail to control free Hb and heme-mediated stress. These protective molecules have pharmacological potential in diverse pathologies including atherosclerosis.

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