Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor–like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis
Objectives-Pericardial fat as a visceral fat depot may be involved in the pathogenesis of coronary atherosclerosis. To gain evidence for that concept we sought to investigate the relation of pericardial fat volumes to risk factors, serum adiponectin levels, inflammatory biomarkers, and the quantity and morphology of coronary atherosclerosis. PϾ0.001). No association was found between BMI and coronary atherosclerosis. PAT volumes Ͼ300 cm 3 were the strongest independent risk factor for coronary atherosclerosis (odds ratio 4.1; CI 3.63 to 4.33) also significantly stronger compared to the Framingham score. We furthermore demonstrated that elevated PAT volumes are significantly associated with low adiponectin levels, low HDL levels, elevated TNF-␣ levels, and hsCRP. Conclusion-In the present study we demonstrated that elevated PAT volumes are associated with coronary atherosclerosis, hypoadiponectinemia, and inflammation and represent the strongest risk factor for the presence of atherosclerosis and may be important for risk stratification and monitoring. Key Words: cardiac CT Ⅲ pericardial fat Ⅲ obesity Ⅲ adiponectin Ⅲ plaque imaging T here is growing evidence that regional visceral fat distribution may contribute to an unfavorable metabolic and cardiovascular risk profile. 1,2 In patients with obesity, insulin resistance, diabetes, and hyperlipidemia visceral fat hypertrophies and transforms into a multifunctional organ that produces and secretes multiple endocrine and paracrine factors promoting inflammation, neovascularization, and oxidative stress, features that also characterize atherosclerosis. 3 Pericardial fat as a local visceral fat depot with close proximity to coronary arteries may serve as a source of inflammatory cytokines and cells that may locally enhance systemic proatherogenic effects via outside to inside signaling. 4,5 Thus it may be a specific parameter indicating an unfavorable cardio-metabolic state and may be used for risk stratification. To date, however, only little attention has focused on this regional fat depot located around the heart and its relation to cardiovascular risk factors, and the quantity and composition of coronary atherosclerosis is not well studied yet. Methods and Results-UsingMulti-slice CT is a noninvasive tool that allows to reliably assess both obstructive and nonobstructive subclinical coronary artery disease in an earlier stage than invasive angiography. 6 -9 Based on density measurements, plaques can be further characterized in noncalcified, mixed, and calcified plaques. 7 By using the same scan data this tool furthermore allows to quantify the exact pericardial fat volume. 9 We thus sought to assess the relation of pericardial fat volume to cardiovascular risk factors, levels of inflammatory cytokines, adiponectin, and to the extent and the phenotype of coronary atherosclerosis.
Objectives: Chemerin is a recently discovered adipokine that regulates adipocyte differentiation and modulates chemotaxis and activation of dendritic cells and macrophages. Given the convergence of adipocyte and macrophage function, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis in humans. We sought to examine the relationship of i) chemerin and markers of inflammation, ii) chemerin and components of the metabolic syndrome, and iii) chemerin and coronary atherosclerotic plaque burden and morphology. Design: Serum chemerin levels were determined in 303 patients with stable typical or atypical chest pain who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed, or non-calcified. Results: Chemerin levels were highly correlated with high sensitivity C-reactive protein (rZ0.44, P!0.0001), interleukin-6 (rZ0.18, PZ0.002), tumor necrosis factor-a (rZ0.24, P!0.0001), resistin (rZ0.28, P!0.0001), and leptin (rZ0.36, P!0.0001) concentrations. Furthermore, chemerin was associated with components of the metabolic syndrome including body mass index (rZ0.23, PZ0.0002), triglycerides (rZ0.29, P!0.0001), HDL-cholesterol (rZK0.18, PZ0.003), and hypertension (P!0.0001). In bivariate analysis, chemerin levels were weakly correlated with coronary plaque burden (rZ0.16, PZ0.006) and the number of non-calcified plaques (rZ0.14, PZ0.02). These associations, however, were lost after adjusting for established cardiovascular risk factors (odds ratio, OR 1.17, 95% confidence interval (CI) 0.97-1.41, PZ0.11 for coronary plaque burden; OR 1.06, 95% CI 0.96-1.17, PZ0.22 for non-calcified plaques). Conclusions: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome. However, chemerin does not predict coronary atherosclerosis.
Hypoglycemia and hyperglycemia are both predictors for adverse outcome in critically ill patients. Hyperinsulinemia is induced by inflammatory stimuli as a relevant mechanism for glucose lowering in the critically ill. The incretine hormone GLP-1 was currently found to be induced by endotoxin, leading to insulin secretion and glucose lowering under inflammatory conditions in mice. Here, we describe GLP-1 secretion to be increased by a variety of inflammatory stimuli, including endotoxin, interleukin-1β (IL-1β), and IL-6. Although abrogation of IL-1 signaling proved insufficient to prevent endotoxin-dependent GLP-1 induction, this was abolished in the absence of IL-6 in respective knockout animals. Hence, we found endotoxin-dependent GLP-1 secretion to be mediated by an inflammatory cascade, with IL-6 being necessary and sufficient for GLP-1 induction. Functionally, augmentation of the GLP-1 system by pharmacological inhibition of DPP-4 caused hyperinsulinemia, suppression of glucagon release, and glucose lowering under endotoxic conditions, whereas inhibition of the GLP-1 receptor led to the opposite effect. Furthermore, total GLP-1 plasma levels were profoundly increased in 155 critically ill patients presenting to the intensive care unit (ICU) in comparison with 134 healthy control subjects. In the ICU cohort, GLP-1 plasma levels correlated with markers of inflammation and disease severity. Consequently, GLP-1 provides a novel link between the immune system and the gut with strong relevance for metabolic regulation in context of inflammation.
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