Targeting endothelial dysfunction in vascular complications associated with diabetes

Abstract

Cardiovascular complications associated with diabetes remain a significant health issue in westernized societies. Overwhelming evidence from clinical and laboratory investigations have demonstrated that these cardiovascular complications are initiated by a dysfunctional vascular endothelium. Indeed, endothelial dysfunction is one of the key events that occur during diabetes, leading to the acceleration of cardiovascular mortality and morbidity. In a diabetic milieu, endothelial dysfunction occurs as a result of attenuated production of endothelial derived nitric oxide (EDNO) and augmented levels of reactive oxygen species (ROS). Thus, in this review, we discuss novel therapeutic targets that either upregulate EDNO production or increase antioxidant enzyme capacity in an effort to limit oxidative stress and restore endothelial function. In particular, endogenous signaling molecules that positively modulate EDNO synthesis and mimetics of endogenous antioxidant enzymes will be highlighted. Consequently, manipulation of these unique targets, either alone or in combination, may represent a novel strategy to confer vascular protection, with the ultimate goal of improved outcomes for diabetes-associated vascular complications.

Figure 1

Under basal conditions, eNOS is kept in a “less active” state by binding to Cav-1. Activation of eNOS occurs by stimuli, (sheer stress, agonists such as acetylcholine, Ach), which causes an increase in intracellular Ca²⁺ and subsequent recruitment of cofactors and phosphorylation of the enzyme at S¹¹⁷⁷. Following which, eNOS is dissociated from Cav-1 and efficient EDNO production occurs. CaM: calmodulin; hsp90: heat shock protein 90.

Figure 2

Pathways activated during hyperglycaemia that limit eNOS function and subsequent NO production, leading to endothelial dysfunction and diabetes-associated vascular disease.

Figure 3

Classic antioxidant pathways for the neutralization of ROS produced by hyperglycaemia in the cytoplasm and mitochondria of endothelial cells. O₂ ^•−: superoxide anion; ONOO⁻: peroxynitrite; NO₂ ⁻: nitrite; H₂O₂: hydrogen peroxide; ^•OH: hydroxyl radicals; LOOH: lipid hydroperoxides; LOH: lipid alcohol; Nox: NADPH oxidase.