Pathological Role of Unsaturated Aldehyde Acrolein in Diabetic Retinopathy

Abstract

With increasing prevalence of diabetes and a progressively aging society, diabetic retinopathy is emerging as one of the global leading causes of blindness. Recent studies have shown that vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of diabetic retinopathy and anti-VEGF agents have become the first-line therapy for the vision-threatening disease. However, recent studies have also demonstrated that diabetic retinopathy is a multifactorial disease and that VEGF-independent mechanism(s) also underlie much of the pathological changes in diabetic retinopathy. Acrolein is a highly reactive unsaturated aldehyde and is implicated in protein dysfunction. As acrolein is common in air pollutants, previous studies have focused on it as an exogenous causative factor, for instance, in the development of respiratory diseases. However, it has been discovered that acrolein is also endogenously produced and induces cell toxicity and oxidative stress in the body. In addition, accumulating evidence suggests that acrolein and/or acrolein-conjugated proteins are associated with the molecular mechanisms in diabetic retinopathy. This review summarizes the pathological roles and mechanisms of endogenous acrolein production in the pathogenesis of diabetic retinopathy.

Keywords: acrolein; diabetic retinopathy; inflammation; oxidative stress; spermine oxidase; vascular adhesion protein-1.

Figure 1

Structures of (A) acrolein and (B) one of the major acrolein-conjugated proteins, N^ϵ-(3-formyl-3, 4-dehydropiperidino) lysine adduct (FDP-Lys).

Figure 2

Enzymatic oxidation of spermine mediated by vascular adhesion protein-1 (VAP-1) function as semicarbazide-sensitive amine oxidase (SSAO). VAP-1 converts spermine to acrolein and hydrogen peroxide, both of which increase oxidative stress in the body.

Figure 3

Sequential steps of release of the soluble form of VAP-1 from retinal capillary endothelial cells. (A) VAP-1 and other leukocyte adhesion molecules facilitate leukocyte recruitment upon inflammation. (B) Recruited leukocytes secrete inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β(IL-1β) and vascular endothelial cell growth factor (VEGF). (C) MMP-2 and MMP-9 induced by the inflammatory cytokines proteolytically cleave the VAP-1 protein. (D) Soluble form of VAP-1 was released from the surface of endothelial cells.

Figure 4

A schematic of oxidative degradation of spermine by spermine oxidase (SMOX). SMOX catalyzes spermine and produces spermidine, hydrogen peroxides, and 3-aminopropanal, which is non-enzymatically converted to acrolein.

Figure 5

A schematic summary illustrating the role of acrolein in diabetic retinopathy.