1065 © Schattauer 2010 Thrombosis and Haemostasis 103.5/2010 Cardiovascular Biology and Cell Signalling Pro-atherothrombotic effects of leptin in human coronary endothelial cells Plinio Cirillo 1 ; Valeria Angri 1 ; Salvatore De Rosa 1 ; Gaetano Calì 2 ; Gianluca Petrillo 1 ; Fabio Maresca 1 ; Greta-Luana D’Ascoli 1 ; Paola Maietta 1 ; Linda Brevetti 1 ; Massimo Chiariello 1 1 Department of Clinical Medicine, Cardiovascular and Immunological Science (Division of Cardiology), University of Naples “Federico II”, Naples, Italy; 2 IEOS “G. Salvatore”, National Council of Research, Naples, Italy Summary Adipocytes are nowadays recognised as cells able to produce and se- crete a large variety of active substances termed adipokines, which exert direct effects on vascular cells. Among these adipokines, leptin has been proposed to play a role in the pathophysiology of acute coron- ary syndromes, as well as in increasing cardiovascular risk. At the mo- ment, however, the mechanisms linking leptin to cardiovascular disease are not completely understood. This study investigates the effects of leptin, in a concentration range usually observed in the plasma of pa- tients with increased cardiovascular risk or measurable in patients with acute coronary syndromes, on tissue factor (TF) and cellular adhesion molecules (CAMs) expression in human coronary endothelial cells (HCAECs). We demonstrate that leptin induces transcription of mRNA for TF and CAMs by real-time PCR. In addition, we show that this adi- pokine promotes surface expression of TF and CAMs that are function- Correspondence to: Plinio Cirillo, MD, PhD Division of Cardiology University of Naples “Federico II”, Via Sergio Pansini 5 80131 Naples, Italy Tel.: +39 081 7462216 2228, Fax: +39 081 7462229 E-mail: pcirillo@unina.it ally active since we observed increased procoagulant activity and leu- kocyte adhesion on cell surface. Leptin effects appear modulated by eNOS-production of oxygen free radicals through the activation of the transcription factor, nuclear factor(NF)-κB, since L-NAME, Superoxide Dismutase and NF-κB inhibitors suppressed CAMs and TF expression. Data of the present study, although in vitro, indicate that leptin may exert direct effects on human coronary endothelial cells by promoting CAMs and TF expression and support the hypothesis that this adipo- kines, besides being involved in the pathophysiology of obesity, might play a relevant role as an active mediator linking obesity to cardiovas- cular disease. Keywords Adhesion molecules, adipokines, atherothrombosis, leptin, obesity, tis- sue factor Received: June 22, 2009 Accepted after major revision: December 30, 2009 Prepublished online: February 19, 2010 doi:10.1160/TH09-06-0392 Thromb Haemost 2010; 103: 1065–1075 Introduction Epidemiological studies have demonstrated that human obesity, is a strong cardiovascular risk factor (1, 2); however, the possible link(s) between these two conditions are not completely under- stood yet. Indeed, emerging evidence have transformed the current point of view about the adipose tissue, indicating that adipocytes have no longer to be considered only storage cells for fat, but they have to be now recognised as cells able to produce and secrete a large variety of active substances, termed adipokines, with pro- atherogenic and pro-inflammatory effects on vascular cells, which could be, in turn, responsible for the increased cardiovascular risk in obese patients. Among these adipokines, leptin, adiponectin and resistin are of particular interest in cardiovascular pathophysiol- ogy (3). In this context, it is of particular interest that obese indi- viduals frequently have elevated plasma levels of leptin (4). Thus it has been recently proposed that this adipokine, involved in the regulation of energy metabolism (5) might be a marker of in- creased cardiovascular risk, since several actions exerted by leptin on cardiovascular system suggest involvement of this adipokine in the development of cardiovascular disease (1, 6–8). Atherothrombosis plays a pivotal role in the pathophysiology of cardiovascular disease and of its complications (9). Indeed, leptin has been demonstrated to promote atherosclerosis and thrombosis in apo-E- deficient mice (6). In addition, leptin-dependent platelet aggregation has been suggested as another potential mechanism linking atherotrombotic disease to obesity (7). One of the major pathogenetic mechanisms of atherosclerosis is the recruitment of circulating leucocytes onto the vessel wall and their subsequent migration into the subendothelial space (10). This phenomenon appears to be mediated by cellular adhesion molecules (CAMs), usually expressed by endothelial cells only in response to pro-inflammatory stimuli (10–12). Among the CAMs, the inter-cellular adhesion molecule-1 (ICAM-1), the vascular cel- lular adhesion molecule-1 (VCAM-1) and E-selectin seem to play a pivotal role in mediating leucocyte transmigration into the sub- endothelial space (13). For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2018-03-23 | ID: 1001066444 | IP: 54.70.40.11