Integrin α_IIbβ₃ exists in an activated state in subjects with elevated plasma homocysteine levels

Abstract

Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease and thrombosis. The molecular basis for this phenomenon is not known but may relate to modification of cell surface thiols. The platelet specific integrin α_IIbβ₃ is a cysteine-rich cell adhesion molecule that plays a critical role in platelet aggregation and adhesion in haemostasis and thrombosis. In this study, we looked for evidence of a homocysteine-induced modification of α_IIbβ₃ using a fluorescently labeled PAC-1 antibody that recognizes the activated conformation of the integrin on the platelet surface. We show that exogenous Hcy (10–100 µM) and homocysteine thiolactone (HcyTL) (10–100 µM) increased PAC-1 binding to platelets in a concentration dependent manner in vitro. In parallel, we show subjects with clinical hyperhomocysteinemia exhibit a greater degree of activation of α_IIbβ₃ compared to age-matched controls. These findings demonstrate that circulating Hcy can modulate the activation state of the platelet integrin α_IIbβ₃, a key player in platelet aggregation and thrombosis.

• Homocysteine
• platelet activation
• integrin α_IIbβ₃