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

Hanene Zbidi; Pedro C. Redondo; Jose J. López; Aghleb Bartegi; Gines M. Salido; Juan A. Rosado

doi:10.1160/TH09-08-0552

Thrombosis and Haemostasis, Table of Contents

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

¹Institute of Biotechnology, University of Monastir, Monastir, Tunisia

,

Pedro C. Redondo

²Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain

,

Jose J. López

²Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain

,

Aghleb Bartegi

¹Institute of Biotechnology, University of Monastir, Monastir, Tunisia

,

Gines M. Salido

²Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain

,

Juan A. Rosado

²Department of Physiology (Cell Physiology Research Group), University of Extremadura, Cáceres, Spain

› Author Affiliations

Abstract

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

Full Text

References

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