Platelet Sarcoplasmic Endoplasmic Reticulum Ca 2+ -ATPase and μ-Calpain Activity Are Altered in Type 2 Diabetes Mellitus and Restored by Rosiglitazone
- 1 January 2008
- journal article
- clinical trial
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 117 (1), 52-60
- https://doi.org/10.1161/circulationaha.107.719807
Abstract
Background— Platelets from patients with type 2 diabetes mellitus display hyperaggregability and increased thrombogenic potential. Methods and Results— In platelets from patients with type 2 diabetes mellitus, we found enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca 2+ -ATPase (SERCA-2), elevated platelet [Ca 2+ ] i , and activation of μ-calpain. The tyrosine nitration of SERCA-2 and the activation of μ-calpain in vitro in platelets from healthy volunteers could be evoked in vitro by peroxynitrite. Platelet endothelial cell adhesion molecule-1 was identified as a μ-calpain substrate; its in vitro degradation was stimulated by peroxynitrite and prevented by calpain inhibitors. Calpain activation also was linked to hyperresponsiveness to thrombin and the loss of platelet sensitivity to nitric oxide synthase inhibitors. Platelets from patients with type 2 diabetes mellitus (hemoglobin A 1c >6.6%) contained little or no intact platelet endothelial cell adhesion molecule-1, whereas degradation products were detectable. The peroxisome proliferator–activated receptor-γ agonist rosiglitazone increased SERCA-2 expression in megakaryocytes, and treating patients with type 2 diabetes mellitus with rosiglitazone for 12 weeks increased platelet SERCA-2 expression and Ca 2+ -ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca 2+ ] i . Rosiglitazone also reduced μ-calpain activity, normalized platelet endothelial cell adhesion molecule-1 levels, and partially restored platelet sensitivity to nitric oxide synthase inhibition. Conclusion— These data identify megakaryocytes/platelets as additional cellular targets for peroxisome proliferator–activated receptor-γ agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.Keywords
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