Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.

OBJECTIVE -Adiponectin is a plasma protein expressed in adipose tissue. Hypoadiponectinemia is associated with low HDL cholesterol and high plasma triglycerides, which also characterize lipoprotein lipase (LPL) deficiency syndromes. Recently, dramatically increased LPL activity was reported in mice overexpressing adiponectin. We therefore speculated that adiponectin may directly affect LPL in humans. RESULTS -Nondiabetic subjects with decreased plasma adiponectin had lower LPL activity (r ϭ 0.42, P Ͻ 0.0001). This association of plasma adiponectin with LPL activity was confirmed in the second group of patients with type 2 diabetes (r ϭ 0.37, P Ͻ 0.0001). Multivariate analysis revealed that adiponectin was the strongest factor influencing LPL activity, accounting for 23% of the variation in LPL activity in nondiabetic subjects and for 26% of the variation in LPL activity in type 2 diabetic patients. These associations were independent of plasma CRP and HOMA-IR. RESEARCH DESIGN AND METHODSCONCLUSIONS -These results demonstrate an association of decreased postheparin LPL activity with low plasma adiponectin that is independent of systemic inflammation and insulin resistance. Therefore, LPL may represent a link between low adiponectin levels and dyslipidemia in both nondiabetic individuals and patients with type 2 diabetes. Diabetes Care 27:2925-2929, 2004L ipoprotein lipase (LPL) is a pivotal enzyme in lipid metabolism (1). Low LPL activity may be observed in the diabetic dyslipidemia of low HDL cholesterol and high plasma triglycerides (2). Plasma LPL activity has been shown to be decreased in insulin-resistant subjects without diabetes (3), and recently, overall plasma LPL activity was inversely associated with insulin resistance in patients with type 2 diabetes (4). LPL expression is also modulated by systemic inflammation. Tumor necrosis factor (TNF)-␣ and interleukin-6 reduce the expression of LPL at the transcriptional level and decrease LPL activity in plasma (5,6).Adiponectin, the gene product of the apM1 (adipose most abundant gene transcript 1) gene (7), is a member of bioactive substances known as adipocytokines. Adiponectin plasma levels are negatively correlated with BMI (8), insulin resistance (9), and type 2 diabetes (9). Furthermore, adiponectin is associated with lower TNF-␣ expression (10) and has been shown to suppress TNF-␣-induced activation of nuclear transcription factor-B (11), thereby demonstrating antiinflammatory potential. Recently published data suggest that low levels of adiponectin are associated with a lipid profile of low HDL cholesterol and increased plasma triglycerides (12) that is also characteristic for the hypertriglyceridemia in LPL deficiency. LPL is mainly expressed in muscle and adipose tissue (1), the unique source of adiponectin. These findings suggest a direct or indirect relationship between LPL and adiponectin by an unknown mechanism. We therefore investigated, in two different groups of patients, whether adiponectin influences LPL plasma activity and concentration an...

It is unclear whether thrombophilia causes resistance to anticoagulant therapy. Post hoc analyses of data from RE-COVER, RE-COVER II, and RE-MEDY were performed to compare dabigatran etexilate with warfarin for the treatment and prevention of venous thromboembolism (VTE) in patients with thrombophilia or antiphospholipid antibody syndrome (APS). There were no significant differences in symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. All bleeding event categories were less frequent with dabigatran etexilate than with warfarin, regardless of whether patients had thrombophilia, no thrombophilia, or were not tested. However, these differences did not reach significance in every group. In patients with APS, there was no significant difference in VTE/VTE-related deaths between the two treatment arms. Rates of bleeding events tended to be lower with dabigatran etexilate than with warfarin, reaching statistical significance for any bleeding event. In conclusion, the efficacy and safety of dabigatran etexilate were not significantly affected by the presence of thrombophilia or APS. ClinicalTrials.gov RECOVER IDENTIFIER NCT00291330; RECOVER II IDENTIFIER NCT00680186; RE-MEDY IDENTIFIER NCT00329238.

Objective-Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation.Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions. Methods and Results-Melagatran (500 mol/kg/d) or control diet was administered to apolipoprotein E-deficient mice (nϭ54) with advanced atherosclerotic lesions. A cute coronary syndromes are related to the formation and disruption of atherosclerotic plaques. Advanced atherosclerotic lesions are characterized by the presence of a lipid rich necrotic core, which is separated from the vessel lumen by a protective fibrous cap. Most acute coronary events result from the rupture of this fragile fibrous cap. As the cap ruptures, the cells and soluble factors of the coagulant system are exposed to this large pool of procoagulant components, resulting in platelet activation and aggregation, thrombin generation, and the development of a large, often occlusive, thrombus. 1,2 There is increasing evidence that thrombin also participates in atherosclerotic heart disease in ways that do not directly involve thrombus formation; it acts as a signaling molecule, through protease-activated receptors. 3 These signaling events concern virtually all aspects of vascular biology, including vessel tone, 4 cell differentiation, 5 migration, 6 proliferation, 7,8 angiogenesis, 9 and vascular pathology such as atherosclerosis and inflammation. 10 -12 In the present study, we tested the hypothesis, whether administration of the direct thrombin inhibitor melagatran prevents initiation of atherosclerosis in C57BL/6J mice and/or alters size and composition of advanced atherosclerotic lesions in hyperlipidemic apolipoprotein E-deficient mice. Methods Animals and Drug TreatmentThirty-week-old female apolipoprotein E-deficient mice (Charles River WIGA, Salzfeld, Germany) 13 (strain name B6.129P2) on a C57BL/6J background (nϭ54) were kept within the animal care facility of the University of Heidelberg. 28 mice were fed a chow diet supplemented with melagatran (500 mol/kg/d) for 22 weeks, 26 mice received regular chow diet. Ximelagatran, which is rapidly bioconverted into its active form, melagatran is generally used in Original

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