Protective role of heme oxygenase-1 against inflammation in atherosclerosis

Abstract

Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting step in the metabolism of free heme into equimolar amounts of ferrous iron, carbon monoxide (CO), and biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. HO-1 has recently been identified as a promising therapeutic target in the treatment of vascular inflammatory disease, including atherosclerosis. HO-1 represses inflammation by removing the pro-inflammatory molecule heme and by generating CO and the bile pigments, biliverdin and bilirubin. These HO-1 reaction products are capable of blocking innate and adaptive immune responses by modifying the activation, differentiation, maturation, and/or polarization of numerous immune cells, including endothelial cells, monocytes/macrophages, dendritic cells, T lymphocytes, mast cells, and platelets. These cellular actions by CO and bile pigments result in diminished leukocyte recruitment and infiltration, and pro-inflammatory mediator production within atherosclerotic lesions. This review highlights the mechanisms by which HO-1 suppresses vascular inflammation in atherosclerosis, and explores possible therapeutic modalities by which HO-1 and its reaction products can be employed to ameliorate vascular inflammatory disease.

Figure 1

The heme oxygenase (HO)-mediated metabolism of heme. HO catalyzes the degradation of heme into equimolar amounts of ferrous heme (Fe²⁺), carbon monoxide (CO), and biliverdin. This oxidative reaction is blocked by various metalloporphyrins, including tin and zinc protoporphyrin-IX. Biliverdin is subsequently metabolized to bilirubin by biliverdin reductase. M, P, and V represent methyl, propionyl, and vinyl groups, respectively; NADPH, nicotinamide adenine dinucleotide phosphate.

Figure 2

Potential mechanisms by which HO-1 inhibits vascular inflammation in atherosclerosis. HO-1 and its reaction products exert potent anti-inflammatory effects on numerous cell types that may inhibit the process of atherogenesis. HO-1 inhibits the recruitment and infiltration of immune cells into the vasculature by suppressing adhesion receptor expression and chemokine production by vascular endothelial cells (ECs) and smooth muscle cells (SMCs). HO-1 also blocks the release of proteases, nitric oxide and pro-inflammatory cytokines from monocytes and the activation and differentiation of macrophages into foam cells by blocking the expression of scavenger receptors and toll-like receptors (TLRs) while inhibiting matrix metalloproteinase (MMPs) activity and stimulating the synthesis of the anti-inflammatory cytokine, interleukin-10 (IL-10). In addition, HO-1 may indirectly affect T lymphocyte (T cell) function by blocking surface expression of major histocompatibility complex class II (MHCII) and the maturation of dendritic cells, and by promoting the activity of T regulatory cells (T_Reg). Moreover, HO-1 may drive T cell differentiation toward a CD4⁺ T cell and a T helper T 2 (T_h2) reaction that limits the production of pro-atherogenic cytokines. Finally, HO-1 also prevents the release of inflammatory mediators from mast cells (histamine, proteases, and pro-inflammatory cytokines) and platelets [interleukin-1β (IL-1β), CD40 ligand (CD40L), chemokines, and MMPs] by inhibiting their activation and degranulation.