Platelets Derived From the Bone Marrow of Diabetic Animals Show Dysregulated Endoplasmic Reticulum Stress Proteins That Contribute to Increased Thrombosis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 9; pp. 2141 - 2148
• Main Authors: Hernández Vera, Rodrigo, Vilahur, Gemma, Ferrer-Lorente, Raquel, Peña, Esther, Badimon, Lina
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2012; Lippincott Williams & Wilkins
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Coagulation; Blood Coagulation Tests; Blood coagulation. Blood cells; Blood Glucose - metabolism; Blood Platelets - metabolism; Blood Platelets - pathology; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone Marrow Transplantation; Cardiology. Vascular system; Diabetes Complications - blood; Diabetes Complications - etiology; Diabetes Complications - pathology; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - pathology; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum Stress; Fundamental and applied biological sciences. Psychology; Green Fluorescent Proteins - biosynthesis; Green Fluorescent Proteins - genetics; Heat-Shock Proteins - metabolism; Medical sciences; Molecular and cellular biology; Platelet; Platelet Activation; Platelet Function Tests; Protein Disulfide-Isomerases - metabolism; Rats; Rats, Transgenic; Rats, Wistar; Rats, Zucker; Thromboplastin - metabolism; Thrombopoiesis; Thrombosis - blood; Thrombosis - etiology; Thrombosis - pathology; Time Factors; Endocrinopathy; Diabetes mellitus; protein disulfide isomerase; Tissue factor; Cardiovascular disease; Glucose; Thrombosis; Stress; Vascular disease; Platelet; Animal; Atherosclerosis; Bone marrow; Endoplasmic reticulum; glucose-related protein 78
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.112.255281

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. METHODS AND 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. CONCLUSION—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.