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Thromb Haemost 2010; 103(05): 1022-1032
DOI: 10.1160/TH09-08-0552
Platelets and Blood Cells
Schattauer GmbH

Homocysteine induces caspase activation by endoplasmic reticulum stress in platelets from type 2 diabetics and healthy donors

Hanene Zbidi
1   Institute of Biotechnology, University of Monastir, Monastir, Tunisia
,
Pedro C. Redondo
2   Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain
,
Jose J. López
2   Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain
,
Aghleb Bartegi
1   Institute of Biotechnology, University of Monastir, Monastir, Tunisia
,
Gines M. Salido
2   Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain
,
Juan A. Rosado
2   Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain
› Author Affiliations Financial support: This study was supported by FundeSalud (PRI08A003), PCI grant A/016208/08 and M.E.C. grant BFU2007–60104. J. J. Lopez was supported by MEC-DGI (BFU2004–00165). P. C. Redondo is supported by MEC-Ramon & Cajal programme (RYC 200700349).
Further Information

Publication History

Received: 11 August 2009

Accepted after major revision: 06 January 2010

Publication Date:
22 November 2017 (online)

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Summary

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, homo-cysteine 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 Ca2+ concentration were determined by fluorimetry. Caspase activity and phosphorylation of the eukaryotic initiation factor 2α (eIF2α) were explored by Western blot. Our results indicate that homocysteine releases Ca2+ from agonist sensitive stores, enhances eIF2α phosphorylation at Ser51 and activates caspase-3 and -9 independently of extracellular Ca2+. Homocysteine induced activation of caspase-3 and -9 was abolished by salubrinal, an agent that prevents endoplasmic reticulum (ER) stress-induced apoptosis. Homo-cysteine-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.

Keywords

Homocysteine - ER stress - caspases - apoptosis - diabetes mellitus
 

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