Integrin α(IIb)β₃ exists in an activated state in subjects with elevated plasma homocysteine levels.
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(IIb)β₃ 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(IIb)β₃ 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(IIb)β₃ compared to age-matched controls. These findings demonstrate that circulating Hcy can modulate the activation state of the platelet integrin α(IIb)β₃, a key player in platelet aggregation and thrombosis.
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Sarah A
SA
McGarrigle
Sarah
S
O'Neill
Geraldine M
GM
Walsh
Niamh
N
Moran
Ian M
IM
Graham
Marie-Therese
MT
Cooney
Ahmad
A
Monavari
Philip
P
Mayne
Patrick
P
Collins
D000906:Antibodies / Q000378:metabolism; D001666:Binding Sites, Antibody / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D016023:Integrins / Q000378:metabolism; D008297:Male; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012307:Risk Factors; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
D000906:Antibodies; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013438:Sulfhydryl Compounds; D006710:Homocysteine; C007957:homocysteine thiolactone