Regulation of thrombosis and vascular function by protein methionine oxidation

Abstract

Redox biology is fundamental to both normal cellular homeostasis and pathological states associated with excessive oxidative stress. Reactive oxygen species function not only as signaling molecules but also as redox regulators of protein function. In the vascular system, redox reactions help regulate key physiologic responses such as cell adhesion, vasoconstriction, platelet aggregation, angiogenesis, inflammatory gene expression, and apoptosis. During pathologic states, altered redox balance can cause vascular cell dysfunction and affect the equilibrium between procoagulant and anticoagulant systems, contributing to thrombotic vascular disease. This review focuses on the emerging role of a specific reversible redox reaction, protein methionine oxidation, in vascular disease and thrombosis. A growing number of cardiovascular and hemostatic proteins are recognized to undergo reversible methionine oxidation, in which methionine residues are posttranslationally oxidized to methionine sulfoxide. Protein methionine oxidation can be reversed by the action of stereospecific enzymes known as methionine sulfoxide reductases. Calcium/calmodulin-dependent protein kinase II is a prototypical methionine redox sensor that responds to changes in the intracellular redox state via reversible oxidation of tandem methionine residues in its regulatory domain. Several other proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, may contribute to vascular disease and thrombosis.

Deficiency of Superoxide Dismutase Impairs Protein C Activation and Enhances Susceptibility to Experimental Thrombosis

“…We speculate that deficiency of cytosolic SOD1 may cause the accumulation of not only superoxide (a charged anion that cannot cross biological membranes) but also other uncharged ROS that can diffuse across the plasma membrane to interact with surface proteins such as TM. 34, 35 …”

Methionine And Antioxidant Potential

“…Metabolome analysis reveals that dietary excess Met increases accumulation of Met oxidation products, such as MetO and Ac-Met sulfoxide (a MetO metabolite) [6]. Previous report suggests that Met oxidation mainly protects critical residues at the active site against oxidative modification of proteins [1].…”

“…kinase II is a prototypical methionine redox sensor and oxidation of paired regulatory domain Met residues enhances its activity by pro-oxidant conditions [1,9], while oxidative stress-induced Met residues oxidation leads to the accumulation of chemically and functionally altered alpha-synuclein with reducing its affinity for biological membranes and impairing degradation the by 20S proteasome [10].…”

“…Met targets reactive oxygen species (ROS) directly by being oxidized to Met sulfoxide (MetO) [1]. Met can be metabolized to cysteine (Cys) through transsulfuration pathway, which is further metabolized to glutathione (GSH), taurine, and hydrogen sulfide (H 2 S).…”

Deletion of Methionine Sulfoxide Reductase A Does Not Affect Atherothrombosis but Promotes Neointimal Hyperplasia and Extracellular Signal-Regulated Kinase 1/2 Signaling

“…4 Methionine oxidation also has been observed to contribute to the redox regulation of several vascular proteins involved in thrombosis and atherosclerosis. 5 These observations suggest that Msr may control specific signaling pathways via the regulation of protein methionine oxidation and reduction. However, despite the well-established role of oxidative stress in vascular diseases such as atherosclerosis, thrombosis and neointimal hyperplasia after mechanical injury, 6 the distinct vascular phenotypes and signaling pathways affected by methionine oxidation in vivo have remained poorly defined.…”