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P-selectin and soluble CD-40-ligand in patients with acute myocardial infarction. Luc Lorgisa*, Sebastien Amoureuxc, Emmanuel de Maistreb, Pierre Sicardc,.

doi: 10.1111/j.1472-8206.2009.00790.x

Fundamental & Clinical Pharmacology

ORIGINAL ARTICLE

Serum brain-derived neurotrophic factor and platelet activation evaluated by soluble P-selectin and soluble CD-40-ligand in patients with acute myocardial infarction Luc Lorgisa*, Sebastien Amoureuxc, Emmanuel de Maistreb, Pierre Sicardc, Yannick Bejotd, Marianne Zellerc, Catherine Vergelyc, Annabelle Sequeira-Le Grande, Anne-Ce´cile Lagrosta, Juliane Berchouda, Yves Cottina,c, Luc Rochettec a

Service de Cardiologie, CHU Bocage, Bd Mal de Lattre de Tassigny, 21034 Dijon, France Service d’He´matologie Biologique, CHU Bocage, Bd Mal de Lattre de Tassigny, 21034 Dijon, France c IFR Sante´-STIC, LPPCE, Universite´ de Bourgogne, 7 Bd Jeanne d’arc, 21079 Dijon, France d Service de Neurologie, CH Ge´ne´ral, Rue Faubourg Raines, 21000 Dijon, France e IFR Sante´-STIC, Plateau technique cytome´trie en flux, Universite´ de Bourgogne, 7 Bd Jeanne d’arc, 21079 Dijon, France b

Keywords acute myocardial infarction, brain-derived neurotrophic factor, soluble CD40 ligand, soluble P-selectin

Received 14 March 2009; revised 19 August 2009; accepted 14 October 2009

*Correspondence and reprints: [email protected]

ABSTRACT

Little is known about the role of neurotrophins (NT) under adult vascular homeostasis in normal and pathological conditions. The NT family, including nerve growth factor and brain-derived neurotrophic factor (BDNF) are expressed in atherosclerotic vessels. Previous studies demonstrated that plasma BDNF levels were increased in the coronary circulation in patients with unstable angina. However, the role of BDNF during the onset and evolution of unstable angina remains to be elucidated. The objective of this study was to evaluate the relationship between BDNF, functional parameters and biological markers associated with inflammatory processes and platelet activation. BDNF serum levels were assessed in patients with acute myocardial infarction (MI) (n = 20) or stable angina pectoris (SAP) (n = 20) who underwent coronary angiography. Serum levels of IL-6, MCP1, sVCAM, soluble CD-40-ligand (sCD40L) and soluble P-selectin (sP-selectin) were measured simultaneously by flux cytometry. Median BDNF levels were higher in the MI than in the SAP group (1730 vs. 877 pg/mL, respectively; P = 0.025). In MI patients, we observed a significant correlation between BDNF and sP-selectin (r = 0.58, P = 0.023), although we found a non-significant trend between BDNF and sCD40L (r = +0.35, P = 0.144). By contrast, no such correlation was observed in SAP patients (r = )0.22, P = 0.425). No difference was observed between the two groups regarding baseline demographics, risk factors, biological data and angiographic findings. The study suggests that BDNF serum levels in MI patients could be related to platelet activation and the inflammatory response. Further studies are needed to investigate the role of NT in the setting of acute MI.

INTRODUCTION Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin (NT) family of proteins that enhance

survival and activity of a large number of non-neuronal cells [1]. Produced and concentrated in the nervous system [2], BDNF play an important role in energy homeostasis as evidenced in recent studies finding the

ª 2009 The Authors Journal compilation ª 2009 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique Fundamental & Clinical Pharmacology 24 (2010) 525–530

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gene encoding BDNF could be involved in syndromic forms of obesity [3]. In the field of cardiovascular disease, the role of BDNF is closely linked with the inflammatory processes which support the development of cardiovascular dysfunction. Then chronic inflammatory disease and atherosclerosis can lead on to modification of the expression and the production of neurotrophine by tissues [4,5]. In particular, it has been shown that BDNF and its receptors [tyrosine-related kinase (Trk)] are expressed in endothelial cells, vascular smooth muscle cells and in atherosclerotic vessels [6,7]. In patients with unstable angina, levels of BDNF are modified in the coronary circulation when compared with stable patients [8,9]. Alternative source of BDNF has been found in macrophages and smooth muscle cells of atheromatous intima and adventitia where BDNF expression is enhanced in the atherosclerotic lesions of unstable angina [8]. But their contribution is believed to be marginal compared with the important release from platelets. Regarding the circulating levels, BDNF levels are 100 times higher in serum than in plasma [10]. Several studies have suggested that BDNF is released by platelets in response to shear stress or agonist stimulation [11,12], but the mechanisms by which platelets stock BDNF are unknown. Moreover, previous studies found a significant correlation between: (i) BDNF and platelet count and (ii) BDNF and age [12]. During thrombus formation, platelets accumulate at the vessel wall, become activated and express P-selectin [13]. This adhesion molecule binds to microparticles that display the P-selectin counter-receptor, termed P-selectin glycoprotein ligand 1, allowing the thrombus to capture microparticles that display tissue factor derived from monocytes [14]. Platelets are the main source of soluble CD-40-ligand (sCD40L), being responsible for >95% of circulating sCD40L levels [15]. This soluble form derives predominantly from activated platelets and thus representing circulating markers of platelet activation [16,17]. The objective of this study was to evaluate the potential relationship between serum BDNF levels, soluble P-selectin (sP-selectin), sCD40 Ligand and functional parameters in patients with coronary artery disease. MATERIALS AND METHODS Patients Forty consecutive patients admitted with either acute myocardial infarction (MI) within 12 h after symptom onset (n = 20) or stable angina pectoris (SAP) with significant stenosis (>75%) (n = 20) who underwent

coronary angiography were recruited. Patients were prospectively enrolled, matched by age and sex. This study complied with the Declaration of Helsinki, was approved by the ethics committee of Dijon University Hospital, and each patient gave written consent before participation. MI was diagnosed according to European Society of Cardiology and American College of Cardiology criteria [18]. Patients with acute infection, acute inflammation, psychological disorders or dementia were excluded from the study. No patients taking antidepressant drugs, major tranquilizers, steroids or non-steroid anti-inflammatory drugs except for aspirin were also excluded. Preanalytical sample processing Coronary angiography took place in the morning following an 8 h fast, during which time peripheral venous blood samples were collected before the injection of a contrast medium. Blood was sampled from the cubital vein, discarding the first 3 mL and collected into heparinized (plasma), additive-free (serum) and EDTAcontaining (for blood cell counts) containers, and centrifuged immediately or within 30 min of venupuncture at 1500 g for 10 min at room temperature. Samples were stored at )80 C until the time of assay (

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