Original article Impaired platelet function reduces myocardial infarct size in Gα q knock-out mice in vivo Hans-Joerg Weig a,c, ⁎ ,1 , Lorenz Bott-Flügel a,1 , Christian Städele b , Kerstin Winter b , Roland Schmidt a , Meinrad Gawaz c , Karl-Ludwig Laugwitz a , Melchior Seyfarth a a Medizinische Klinik, Molekulare Kardiologie, Klinikum rechts der Isar und Deutsches Herzzentrum, Technische Universität, Munich, Germany b Institut für Experimentelle Onkologie und Therapieforschung, Klinikum rechts der Isar, Technische Universität, Munich, Germany c Medizinische Klinik, Eberhard Karls Universität, Tübingen, Germany Received 21 July 2007; received in revised form 10 September 2007; accepted 28 September 2007 Abstract Platelet aggregation and secretion play a crucial role in acute coronary syndromes. In Gα q knock-out mice (Gα q (-/-)) platelet function is eliminated in terms of aggregation and secretion of cytokines. We investigated whether restricted platelet aggregation and secretion reduces myocardial infarct size in vivo. Thirty minute regional myocardial ischemia was followed by 24 h reperfusion (I/R) in vivo. Infarct size was determined by counterstaining. Left ventricular function was measured by ultrasound. Infarct size to area at risk ratio was significantly smaller in Gα q (-/-) mice (5.6 ± 1.6%) compared to wild-type (WT) mice (27.2 ± 3.0%, p b 0.01). Fractional shortening was improved in Gα q (-/-) mice compared to WT (42.2 ± 1.4% versus 30.5 ± 1.4%, respectively, p b 0.01). WT mice, transplanted with Gα q (-/-) bone marrow showed a significant reduction in infarct size compared to control (7.8 ± 2.2% versus 18.4 ± 2.7%, respectively, p b 0.01). Platelets of Gα q (-/-) mice had an impaired aggregation and secretion phenotype. In the in vivo model of ischemia and reperfusion, beyond impaired platelet aggregation, platelet secretion plays an additional role in myocardial infarct extension. Blocking platelet aggregation in combination with secretion might be a promising supplementary therapeutic strategy in acute myocardial infarction. © 2007 Elsevier Inc. All rights reserved. Keywords: Platelets; Aggregation and secretion; Myocardial infarction; G protein coupled receptor; Gα q knock-out 1. Introduction Acute plaque rupture with subsequent adhesion and aggrega- tion of blood platelets resulting in thrombus formation is consi- dered the pathophysiologic basis of acute coronary syndromes [1]. Platelets mediate thrombotic occlusion of the entire epicardial coronary artery and accumulate in the microcirculation resulting in impaired blood flow of the capillaries, thereby provoking myocardial damage during reperfusion [2]. Platelets are initially tethered to the surface through the interaction between membrane glycoprotein Ibα and von Willebrand factor bound to collagen [3]. Consecutively platelet adhesion and activation are triggered by binding of collagen to several platelet-membrane proteins [4,5], including integrin-α 2 β 1 , leading to platelet activation through the release of Thromboxan A 2 (TxA 2 ) and Adenosine- diphosphat (ADP). Activated platelets bind to T lymphocytes, neutrophils and monocytes, and interact with endothelial cells, thus enhancing the sequestration of leukocytes in peripheral tissues contributing to myocardial reperfusion injury [6–8]. Furthermore, activated platelets secrete plenty of granule contents like chemokines (e.g. RANTES, platelet factor 4), cytokine-like factors (e.g. interleukine-1β, CD40-Ligand, β-thromboglobu- line) and coagulation factors (e.g. factor V, factor XI, PAI-1, plasminogen, proteins). These proteins act in a concerted manner and influence widely differing biological functions such as cell adhesion, cell aggregation, chemotaxis, cell survival and proli- feration, coagulation and proteolysis [9]. The platelet activators Thrombin, TxA 2 and ADP activate G q protein coupled receptors Available online at www.sciencedirect.com Journal of Molecular and Cellular Cardiology xx (2007) xxx – xxx + MODEL YJMCC-06177; No. of pages: 8; 4C: 5, 6, 7 www.elsevier.com/locate/yjmcc ⁎ Corresponding author. Medizinische Klinik, Molekulare Kardiologie, Klinikum rechts der Isar, Ismaningerstr. 22, 81675 Munich, Germany. Tel.: +49 89 4140 6901; fax +49 89 4140 4901. E-mail address: Hans-Joerg.Weig@med.uni-tuebingen.de (H.-J. Weig). 1 Hans-Joerg Weig and Lorenz Bott-Flügel contributed equally to this work. 0022-2828/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2007.09.018 ARTICLE IN PRESS Please cite this article as: Weig H-J, et al, Impaired platelet function reduces myocardial infarct size in Gα q knock-out mice in vivo, J Mol Cell Cardiol (2007), doi:10.1016/j.yjmcc.2007.09.018