title: Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis.
abstract: OBJECTIVE
  Patients with diabetes mellitus have an increased risk of suffering atherothrombotic syndromes and are prone to clustering cardiovascular risk factors. However, despite their dysregulated glucose metabolism, intensive glycemic control has proven insufficient to reduce thrombotic complications. Therefore, we aimed to elucidate the determinants of thrombosis in a model of type 2 diabetes mellitus with cardiovascular risk factors clustering.
  
  
  RESULTS
  Intravital microscopy was used to analyze thrombosis in vivo in Zucker diabetic fatty rats (ZD) and lean normoglycemic controls. Bone marrow (BM) transplants were performed to test the contribution of each compartment (blood or vessel wall) to thrombogenicity. ZD showed significantly increased thrombosis compared with lean normoglycemic controls. BM transplants demonstrated the key contribution of the hematopoietic compartment to increased thrombogenicity. Indeed, lean normoglycemic controls transplanted with ZD-BM showed increased thrombosis with normal glucose levels, whereas ZD transplanted with lean normoglycemic controls-BM showed reduced thrombosis despite presenting hyperglycemia. Significant alterations in megakaryopoiesis and platelet-endoplasmic reticulum stress proteins, protein disulfide isomerase and 78-kDa glucose-regulated protein, were detected in ZD, and increased tissue factor procoagulant activity was detected in plasma and whole blood of ZD.
  
  
  CONCLUSIONS
  Our results indicate that diabetes mellitus with cardiovascular risk factor clustering favors BM production of hyperreactive platelets with altered protein disulfide isomerase and 78-kDa glucose-regulated protein expression that can contribute to increase thrombotic risk independently of blood glucose levels.
authors: Cardiovascular Research Center, c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors: Rodrigo
authors: R
authors: Hernández Vera
authors: Gemma
authors: G
authors: Vilahur
authors: Raquel
authors: R
authors: Ferrer-Lorente
authors: Esther
authors: E
authors: Peña
authors: Lina
authors: L
authors: Badimon
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D001786:Blood Glucose / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D048909:Diabetes Complications / Q000097:blood / Q000209:etiology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism*; D015539:Platelet Activation; D010979:Platelet Function Tests; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D011924:Rats, Zucker; D013925:Thromboplastin / Q000378:metabolism; D034061:Thrombopoiesis; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D013997:Time Factors; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D001786:Blood Glucose; D049452:Green Fluorescent Proteins; D006360:Heat-Shock Proteins; D019704:Protein Disulfide-Isomerases; D013925:Thromboplastin; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP