Hemoglobin Oxidation and Heme in Atherosclerosis—Link Between Intraplaque Hemorrhage and Progression of Complicated Atherosclerotic Lesion

Significance: Solid evidence has demonstrated the pathophysiologic role of hemoglobin (Hb) oxidation and heme in the remodeling of arterial tissue in complicated atherosclerotic lesions with hemorrhage. Oxidation of Hb to ferric and ferryl states and subsequent accumulation of ferryl hemoglobin, heme released from globin, peptides derived from fragmentation of globin result in cellular activation and dysfunction, as well as polarization of resident cells and macrophages—all of which drive plaque formation and instability. Recent Advances: Oxidized Hb and heme are endogenous pro-atherogenic agonists that target vascular endothelial cells, smooth muscle cells, neutrophils, and macrophages. Rearrangement of the actin cytoskeleton, disruption of intercellular integrity, activation of proinflammatory genes involving nuclear factor kappa B, the c-Jun N-terminal kinase, and the p38 mitogen-activated protein kinase signal transduction pathways are key events leading to endothelial dysfunction. Polarization of macrophages involves cellular responses toward inflammation, calcification, and angiogenesis. Pathways affected include gene changes associated with phosphoinositide 3-kinase signaling, lipid transport, tissue remodeling, and vascularization. This review focuses on the maladaptive cellular responses to Hb oxidation and its products, together with oxidation of low-density lipoprotein and plaque lipid material implicated in the progression of the complicated atherosclerotic lesion, and provides insights into the potential adaptive molecular mechanisms. Critical Issues: Identification of molecular targets and novel therapeutic applications are needed to prevent remodeling of vascular tissue in the hemorrhaged complicated atherosclerotic lesion. Future Directions: Future research should focus on the red blood cell infiltration of early lesions as a source of extracellular Hb-bearing danger signals. Antioxid. Redox Signal. 00, 000–000.