Published Online
on December 10, 2007

A more recent version of this article appeared on January 1, 2008

This Article Full Text (PDF) Data Supplement All Versions of this Article: 117/1/52    most recent CIRCULATIONAHA.107.719807v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Randriamboavonjy, V. Articles by Fleming, I. Search for Related Content PubMed PubMed Citation Articles by Randriamboavonjy, V. Articles by Fleming, I. Related Collections Aggregation Signal transduction Type 2 diabetes Platelets Related Article

Submitted on June 5, 2007
Accepted on October 19, 2007

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, and 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.

^* To whom correspondence should be addressed. E-mail: fleming{at}em.uni-frankfurt.de.

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.

Key words: CD31 antigens • platelets • PPAR gamma • sarcoplasmic reticulum • sarcoplasmic reticulum calcium-transporting ATPases

Related Article:

Clinical Summaries
Circulation 2008 117: 1-3. [Extract] [Full Text]

This article has been cited by other articles:

				E. Barbosa-Sicard, T. Fromel, B. Keseru, R. P. Brandes, C. Morisseau, B. D. Hammock, T. Braun, M. Kruger, and I. Fleming Inhibition of the Soluble Epoxide Hydrolase by Tyrosine Nitration J. Biol. Chem., October 9, 2009; 284(41): 28156 - 28163. [Abstract] [Full Text] [PDF]

				S. Ahmad, A. Ahmad, E. S. Dremina, V. S. Sharov, X. Guo, T. N. Jones, J. E. Loader, J. R. Tatreau, A.-L. Perraud, C. Schoneich, et al. Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase Expression in Cystic Fibrosis Airways: Role in Oxidant-mediated Cell Death Am. J. Respir. Crit. Care Med., May 1, 2009; 179(9): 816 - 826. [Abstract] [Full Text] [PDF]

				V. Randriamboavonjy and I. Fleming Insulin, Insulin Resistance, and Platelet Signaling in Diabetes Diabetes Care, April 1, 2009; 32(4): 528 - 530. [Full Text] [PDF]

				A. Borbely, I. Falcao-Pires, L. van Heerebeek, N. Hamdani, I. Edes, C. Gavina, A. F. Leite-Moreira, J. G.F. Bronzwaer, Z. Papp, J. van der Velden, et al. Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium Circ. Res., March 27, 2009; 104(6): 780 - 786. [Abstract] [Full Text] [PDF]

				A. Borbely, L. van Heerebeek, and W. J. Paulus Transcriptional and Posttranslational Modifications of Titin: Implications for Diastole Circ. Res., January 2, 2009; 104(1): 12 - 14. [Full Text] [PDF]

				L. van Heerebeek, N. Hamdani, M. L. Handoko, I. Falcao-Pires, R. J. Musters, A. Borbely, J. van der Velden, G. J.M. Stienen, W. J. Paulus, J. G.F. Bronzwaer, et al. Response to Letter Regarding Article, "Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension" Circulation, June 10, 2008; 117(23): e484 - e484. [Full Text] [PDF]