Effects of exercise training on high-mobility group box-1 levels after acute myocardial infarction.

BACKGROUND: High-mobility group box-1 (HMGB1) is a novel predictor of adverse postinfarction clinical outcomes, playing a crucial role in the appropriate postinfarction healing process. METHODS AND RESULTS: Seventy-five postinfarction patients were enrolled in a single-center randomized study (clinicaltrial.gov identifier: NCT00755131). Group T patients (training, n = 37) underwent 6-month exercise-based cardiac rehabilitation (CR) program, whereas group C patients (controls, n = 38) were discharged with generic instructions for maintaining physical activity and a correct lifestyle. After 6 months, HMGB1 levels were significantly reduced in the total population (26.1 ± 23.5 vs. 16.2 ± 12.9 ng/mL; P = .0006). After adjusting for several confounders, linear regression analysis showed that the inclusion in the training group (ß = -10.54, P = .043) was associated with marked reduction of HMGB1 levels. After 6 months, HMGB1 levels were significantly lower in trained patients compared to controls (11.7 ± 7.0 vs. 20.5 ± 15.6 ng/mL, P = .0027, respectively). In trained patients, decreased HMGB1 levels were significantly associated with the improvement in peak oxygen consumption (ß = -3.879, P = .003) and heart rate recovery (ß = -2.492, P = .002), and with reduced left ventricular end-diastolic volume (ß = 1.412, P = .001) and wall motion score index (ß = 1.138, P = .002). CONCLUSIONS: The decrease in HMGB1 levels after anterior myocardial infarction was associated with exercise training and with the improvement of cardiopulmonary and autonomic function, and with favorable cardiac remodeling.

Pro-atherothrombotic effects of leptin in human coronary endothelial cells.

Adipocytes are nowadays recognised as cells able to produce and secrete 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 coronary syndromes, as well as in increasing cardiovascular risk. At the moment, 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 patients 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 adipokine promotes surface expression of TF and CAMs that are functionally active since we observed increased procoagulant activity and leukocyte 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)-kappaB, since L-NAME, Superoxide Dismutase and NF-kappaB 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 adipokines, besides being involved in the pathophysiology of obesity, might play a relevant role as an active mediator linking obesity to cardiovascular disease.

HMG-CoA reductase inhibitors reduce nicotine-induced expression of cellular adhesion molecules in cultured human coronary endothelial cells.

BACKGROUND: Smoking predisposes to the development of atherosclerosis and of its complications. The mechanisms responsible for these effects are not completely understood. We have investigated whether nicotine might promote a proatherosclerotic state in human coronary endothelial cells (HCAECs), studying the role of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in preventing these phenomena. METHODS AND RESULTS: Real-time PCR showed that nicotine induced a dose-dependent increase in mRNA levels for vascular cellular adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1). Fluorescent-activated cell sorting analysis showed that nicotine induced expression of functionally active VCAM-1/ICAM-1, since they increased leukocyte adherence to HCAECs. Oxygen free radicals, Rho A and nuclear factor kappaB (NF-kappaB) play a pivotal role in modulating these effects. Indeed, nicotine caused oxygen free radical production as well as activation of Rho A and NF-kappaB pathways, evaluated by malondialdehyde levels, pulldown assay and by electrophoretic mobility shift assay, respectively. Superoxide dimutase, Rho A (Y-27639) and NF-kappaB inhibitors (pyrrolidine dithiocarbamate ammonium, Bay 11-7082) suppressed nicotine effects on CAM expression. HMG-CoA reductase inhibitors prevented these nicotine-mediated effects by inhibiting free radical generation and by modulating activation of Rho A and NF-kappaB pathways. CONCLUSIONS: Nicotine promotes CAM expression on HCAECs, shifting them toward a proatherosclerotic state. These effects might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking. HMG-CoA reductase inhibitors play an important role in preventing these phenomena.

C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation.

OBJECTIVE: Inflammation plays a pivotal role in atherothrombosis. In addition to being a prognostic marker for major cardiovascular events, recent data indicate that C-reactive protein (CRP) might directly promote atherothrombosis by exerting direct effects on vascular cells. The aim of the present study was to determine whether CRP might affect the prothrombotic and proliferative characteristics of endothelial (ECs) and smooth muscle cells (SMCs). METHODS AND RESULTS: Incubation of ECs and SMCs with CRP resulted in a dose-dependent activation of cell proliferation, which was mediated by activation of the p44/42 MAP Kinase (ERK 1/2) pathway. In addition, CRP also induced tissue factor (TF) expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real time PCR. Activation of the transcription factor, NF-kappaB, by CRP was demonstrated by EMSA and by suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium. CONCLUSIONS: These data indicate that CRP exerts direct effects on ECs and SMCs by promoting proliferation and TF expression and support the notion that CRP, besides representing a marker of inflammation, is an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the vessel wall.