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(Circulation. 2008;117:52-60.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Platelet Sarcoplasmic Endoplasmic Reticulum Ca²⁺-ATPase and µ-Calpain Activity Are Altered in Type 2 Diabetes Mellitus and Restored by Rosiglitazone

Voahanginirina Randriamboavonjy, PhD; Frank Pistrosch, MD; Birgit Bölck, PhD; Robert H.G. Schwinger, MD; Madhulika Dixit, PhD; Klaus Badenhoop, MD; Richard A. Cohen, MD; Rudi Busse, MD, PhD; Ingrid Fleming, PhD

From the Vascular Signaling Group (V.R., M.D., R.B., I.F.), and Institut für Kardiovaskuläre Physiologie, and Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism (K.B.), Johann Wolfgang Goethe–Universität, Frankfurt, Germany; Department of Medicine (F.P.), Nephrology, University Hospital "Carl Gustav Carus," Dresden, Germany; Laboratory of Muscle Research and Molecular Cardiology (B.B., R.H.G.S.), Department of Internal Medicine III, University of Cologne, Cologne, Germany; and Vascular Biology Unit (R.A.C.), Boston University Medical Center, Boston, Mass. Dr Schwinger is currently affiliated with Klinikum Weiden, Weiden, Germany.

Correspondence to Professor Dr Ingrid Fleming, Vascular Signaling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe–Universität, Theodor–Stern–Kai 7, D–60590 Frankfurt am Main, Germany. E-mail fleming{at}em.uni-frankfurt.de

Received June 5, 2007; accepted October 19, 2007.

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 Ca²⁺-ATPase (SERCA-2), elevated platelet [Ca²⁺]_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- 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 Ca²⁺-ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca²⁺]_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- agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.

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