Inflammation and coagulation in atherosclerosis.

Cardiovascular diseases remain to be the leading cause of death in Western societies. Despite major findings in vascular biology that lead to a better understanding of the pathomechanisms involved in atherosclerosis, treatment of the disease has only changed slightly within the last years. A big body of evidence suggests that atherosclerosis is a chronic inflammatory disease of the vessel wall. Accumulation and peroxidation of LDL-particles within the vessel wall trigger a strong inflammatory response, causing macrophage and T-cell accumulation within the vessel wall. Additionally, B-cells and specific antibodies against LDL-particles, as well as the complement system are implicated in atherogenesis. Besides data from clinical trials and autopsy studies it was the implementation of mouse models of atherosclerosis and the emerging field of direct gen-modification that lead to a thorough description of the pathophysiological mechanisms involved in the disease and created overwhelming evidence for a participation of the immune system. Recently, the cross-talk between coagulation and inflammation in atherogenesis has gained attention. Serious limitations and disparities in the pathophysiology of atherosclerosis in mice and men complicated the translation of experimental data into clinical practice. Despite these limitations, new anti-inflammatory medical therapies in cardiovascular disease are currently being tested in clinical trials.

High soluble Fas and soluble Fas Ligand serum levels before stent implantation are protective against restenosis.

Percutaneous coronary intervention (PCI) represents the most important treatment of coronary artery stenosis today. But instent restenosis (ISR) is a limitation for the outcome. Fas and Fas Ligand have been implicated in apoptosis and vessel wall inflammation. Their role in ISR is not known so far. In this prospective study we studied 137 patients with stable coronary artery disease who underwent elective PCI. Blood samples were taken directly before and 24 hours after PCI. Soluble (s)Fas and sFas Ligand serum levels were measured by ELISA. Restenosis was evaluated six to eight months later either by coronary angiography or by exercise testing. During the follow-up period, 18 patients (13%) developed ISR. At baseline, patients with ISR had significantly lower median sFas, as well as sFas Ligand levels compared to patients without ISR (sFAS: ISR 492 pg/ml, no ISR 967 pg/ml, p=0.014; sFAS Ligand: ISR: 26 pg/ml, no ISR: 42 pg/ml, p=0.001). After PCI median sFas levels significantly decreased in patients with ISR compared to patients without ISR [ISR: -152 pg/ml (IQR -36 to -227), no ISR: -38 pg/ml (IQR -173 to +150 pg/ml), p=0.03]. sFas Ligand levels after PCI significantly increased in ISR patients compared to patients without ISR [ISR: 14 pg/ml (IQR -3 to +26 pg/ml), no ISR -6 pg/ml (IQR -22 to +21 pg/ml), p=0.014]. In conclusion, sFas and sFas Ligand seem to be associated with the development of ISR. Determination of serum levels before and after PCI might help identifying patients at higher risk of ISR.

Complement in atherosclerosis: friend or foe?

Atherosclerosis is a chronic inflammatory disease and the complement system plays a central role in innate immunity. Increasing evidence exists that the complement system is activated within atherosclerotic plaques. However, the role of complement in atherogenesis is not fully understood. Whereas complement activation by the classic and lectin pathway may be protective by removing apoptotic cells and cell debris from atherosclerotic plaques, activation of the complement cascade by the alternative pathway and beyond the C3 convertase with formation of anaphylatoxins and the terminal complement complex may be proatherogenic and may play a role in plaque destabilization leading to its rupture and the onset of acute cardiovascular events. In this review article we present evidence for complement activation within atherosclerotic plaques and we discuss recent data derived from experimental animal models that suggest a dual role of complement in the development of the disease. In addition, we summarize the role of complement components as biomarkers for cardiovascular disease.

Plasminogen activator inhibitor-1 predicts coronary in-stent restenosis of drug-eluting stents.

BACKGROUND: We tested the hypothesis that plasma levels of plasminogen activator inhibitor-1 (PAI-1) are influenced by percutaneous coronary intervention (PCI) with the implantation of drug eluting stents (DES) and are able to predict the occurrence of in-stent restenosis (ISR). METHODS AND RESULTS: PAI-1 active antigen plasma levels were determined in 75 patients before and 24 h after PCI with DES implantation. Patients with ISR after six to eight months (16%) showed significantly lower PAI-1 plasma levels before PCI (ISR, 11.7 +/- 8.1 ng mL(-1); non-ISR, 22.8 +/- 18.8 ng mL(-1); P <0.05). PAI-1 levels in the lowest tertile were associated with a 9.5-fold increased risk of ISR, independent of clinical risk factors, angiographic or procedural characteristics, compared to the highest tertile (P < 0.05). The induced change of PAI-1 active antigen 24 h after PCI was significantly higher in patients with ISR (ISR, +5.6 +/- 8.0 ng mL(-1); non-ISR, -3.2 +/- 12.1 ng mL(-1); P < 0.05) with positive correlation to late lumen loss (r = 0.30; P < 0.05). CONCLUSIONS: ISR after DES implantation is significantly related to plasma levels of PAI-1 active antigen before and after PCI. If confirmed by larger multicenter studies, the determination of PAI-1 plasma levels might be clinically helpful in the identification of patients at high risk of developing of ISR, even after DES implantation.

Vascular endothelial growth factor is induced by the inflammatory cytokines interleukin-6 and oncostatin m in human adipose tissue in vitro and in murine adipose tissue in vivo.

OBJECTIVES: It is believed that adipose tissue acts as an endocrine organ by producing inflammatory mediators and thereby contributes to the increased cardiovascular risk seen in obesity. A link between adipose tissue mass and angiogenesis has been suggested. Vascular endothelial growth factor (VEGF) seems to be implicated in this process. Members of the glycoprotein (gp)130 ligand family regulate VEGF expression in other cells. METHODS AND RESULTS: We used tissue explants as well as primary cultures of preadipocytes and adipocytes from human subcutaneous and visceral adipose tissue to investigate whether the gp130 ligands oncostatin M (OSM), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1) regulate VEGF expression in human adipose tissue. Human subcutaneous and visceral adipose tissue responded to treatment with IL-6 and OSM with a significant increase in VEGF production. Human preadipocytes were isolated from subcutaneous and visceral adipose tissue. Adipocyte-differentiation was induced by hormone-supplementation. All cell types responded to IL-6 and OSM with a robust increase in VEGF protein production and a similar increase in VEGF-specific mRNA. Furthermore, IL-1beta synergistically enhanced the effect of OSM on VEGF production. AG-490, a JAK/STAT inhibitor, abolished the OSM-dependent VEGF induction almost completely. In mice, IL-6 and OSM increased serum levels of VEGF and VEGF mRNA and vessel density in adipose tissue. CONCLUSION: We speculate that the inflammatory cytokines IL-6 and OSM might support angiogenesis during adipose tissue growth by upregulating VEGF.

The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-kappaB activation.

BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory disorder. Activation of the complement cascade is a major aspect of chronic inflammatory diseases. Complement components were identified in atherosclerotic plaques, and a correlation between adverse events and C5a plasma levels was found. These findings support the notion that complement activation contributes to development and progression of atherosclerotic lesions. OBJECTIVES: We investigated whether complement components C3a and C5a regulate plasminogen activator inhibitor (PAI-1) in human macrophages. METHODS: Human monocyte-derived macrophages (MDM) and human plaque macrophages were cultured and incubated with the complement component C5a. RESULTS: C5a increased PAI-1 up to 11-fold in human MDM and up to 2.7-fold in human plaque macrophages. These results were confirmed at the mRNA level using real time-polymerase chain reaction. Pertussis toxin or anti-C5aR/CD88 antibody completely abolished the effect of recombinant human C5a on PAI-1 production, suggesting a role of the C5a receptor. Experiments with antitumor necrosis factor (TNF)-alpha antibodies and tiron showed that the effect of C5a was not mediated by TNF-alpha or oxidative burst. Furthermore C5a induced NF-kappaB binding to the cis element in human macrophages and the C5a-induced increase in PAI-1 was completely abolished by an NF-kappaB inhibitor. CONCLUSIONS: We conclude that C5a upregulates PAI-1 in macrophages via NF-kappaB activation. We hypothesize that - if operative in vivo- this effect could favor thrombus development and thrombus stabilization in the lesion area. On the other hand one could speculate that C5a-induced upregulation of PAI-1 in plaque macrophages could act as a defense mechanism against plaque destabilization and rupture.

Inflammatory cytokines interleukin-6 and oncostatin m induce plasminogen activator inhibitor-1 in human adipose tissue.

BACKGROUND: Adipose tissue is a prominent source of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of plasminogen activation. Increased PAI-1 expression acts as a cardiovascular risk factor, and plasma levels of PAI-1 strongly correlate with body mass index (BMI). Elevated serum levels of interleukin-6 (IL-6), an inflammatory cytokine and a member of the glycoprotein 130 (gp130) ligand family, are found in obese patients and might indicate low-grade systemic inflammation. Another gp130 ligand, oncostatin M (OSM), upregulates PAI-1 in cardiac myocytes, astrocytes, and endothelial cells. We used tissue explants and primary cultures of preadipocytes and adipocytes from human subcutaneous and visceral adipose tissue to investigate whether IL-6 and OSM affect PAI-1 expression in fat. METHODS AND RESULTS: Human subcutaneous and visceral adipose tissue responded to treatment with IL-6 and OSM with a significant increase in PAI-1 production. Human preadipocytes were isolated from subcutaneous and visceral adipose tissue. Adipocyte differentiation was induced by hormone supplementation. All cell types expressed receptors for IL-6 and OSM and produced up to 12-fold increased levels of PAI-1 protein and up to 9-fold increased levels of PAI-1 mRNA on stimulation with IL-6 and OSM. AG-490, a janus kinase/signal transducer and activator of transcription inhibitor, abolished the OSM-dependent PAI-1 induction almost completely. CONCLUSIONS: We have for the first time established a link between the gp130 ligands, the proinflammatory mediators IL-6 and OSM, and the expression of PAI-1 in human adipose tissue. Thus, we speculate that IL-6 and OSM, by upregulating PAI-1 in adipose tissue, can contribute to the increased cardiovascular risk of obese patients.