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

Thromb Haemost. 2010 May;103(5):1022-32. doi: 10.1160/TH09-08-0552. Epub 2010 Mar 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Blood Donors
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Blood Platelets / pathology
  • Calcium Signaling / drug effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Caspase 9 / genetics
  • Caspase 9 / metabolism
  • Cells, Cultured
  • Cinnamates / pharmacology
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Angiopathies / metabolism*
  • Diabetic Angiopathies / pathology
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation / drug effects
  • Homocysteine / metabolism*
  • Humans
  • Hyperhomocysteinemia / etiology
  • Hyperhomocysteinemia / metabolism*
  • Hyperhomocysteinemia / pathology
  • Stress, Physiological / drug effects
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology
  • eIF-2 Kinase / metabolism

Substances

  • Cinnamates
  • salubrinal
  • Homocysteine
  • eIF-2 Kinase
  • Caspase 3
  • Caspase 9
  • Thiourea