Homocysteine induces caspase activation by endoplasmic reticulum stress in platelets from type 2 diabetics and healthy donors.
Diabetes mellitus is a disease characterised by hyperglycaemia and associated with several cardiovascular disorders, including angiopathy and platelet hyperactivity, which are major causes of morbidity and mortality in type 2 diabetes mellitus. In type 2 diabetic patients, homocysteine levels are significantly increased compared with healthy subjects. Hyperhomocysteinaemia is an independent risk factor for macro- and microangiopathy and mortality. The present study is aimed to investigate the effect of homocysteine on platelet apoptosis. Changes in cytosolic or intraluminal free Ca(2+) concentration were determined by fluorimetry. Caspase activity and phosphorylation of the eukaryotic initiation factor 2alpha (eIF2alpha) were explored by Western blot. Our results indicate that homocysteine releases Ca(2+) from agonist sensitive stores, enhances eIF2alpha phosphorylation at Ser(51) and activates caspase-3 and -9 independently of extracellular Ca(2+). Homocysteine induced activation of caspase-3 and -9 was abolished by salubrinal, an agent that prevents endoplasmic reticulum (ER) stress-induced apoptosis. Homocysteine-induced platelet effects were significantly greater in type 2 diabetics than in healthy subjects. These findings demonstrate that homocysteine induces ER stress-mediated apoptosis in human platelets, an event that is enhanced in type 2 diabetic patients, which might be involved in the pathogenesis of cardiovascular complications associated with type 2 diabetes mellitus.
Zbidi
Hanene
H
Institute of Biotechnology, University of Monastir, Monastir, Tunisia.
Redondo
Pedro C
PC
López
Jose J
JJ
Bartegi
Aghleb
A
Salido
Gines M
GM
Rosado
Juan A
JA
D017209:Apoptosis / Q000187:drug effects; D001782:Blood Donors; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism
D002934:Cinnamates; C496827:salubrinal; D006710:Homocysteine; D019892:eIF-2 Kinase; D053148:Caspase 3; D053453:Caspase 9; D013890:Thiourea