Objective-3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. We investigated the effect of statins on the expression of TM and TF by endothelial cells. Methods and Results-The incubation of endothelial cells with pitavastatin led to a concentration-and time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the expression of TF mRNA was not induced under the same conditions. A nuclear run-on study revealed that pitavastatin accelerates TM transcription rate. Key Words: endothelium Ⅲ thrombomodulin Ⅲ statins Ⅲ small GTPase V ascular endothelial cells play an active role in the regulation of blood coagulation and fibrinolysis. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. TM is a high-affinity receptor for thrombin that is present on endothelial cell surfaces. By forming a complex with thrombin, TM alters the procoagulant activity of thrombin and acts as a cofactor for the thrombin-catalyzed activation of circulating protein C. Activated protein C functions as an anticoagulant via the proteolytic degradation of the coagulation factors Va and VIIIa, thereby limiting the generation of thrombin. Thus, the TM-protein C pathway is a major antithrombotic mechanism present in endothelial cells, and TM is important in regulating the fluidity of circulating blood.Tissue factor (TF), a membrane glycoprotein receptor that specifically binds factors VII or VIIa, functions as a cellular trigger of the coagulation cascade via activation of factors X and IX. Under normal circumstances, endothelial cells do not display TF activity. Thus, the normal vascular endothelium is relatively inert with respect to initiation of coagulation. A procedure to enhance upregulation of TM without induction of TF expression in cells provides an important clue toward the therapy and prevention of vascular thrombosis. 1 Activated protein C also functions as an important modulator of inflammation associated with severe sepsis. 2 In vitro data indicate that activated protein C exerts an anti-inflammatory effect by both inhibiting the production of inflammatory cytokines (tumor necrosis factor-␣, interleukin-1, and interleukin-6) by monocytes and limiting the rolling of monocytes and neutrophils on injured endothelium via selectin binding. 3 Activated protein C indirectly increases the fibrinolytic response by inhibiting plasminogen activator inhibitor. Recently, it has been shown that treatment with activated protein C significantly reduced mortality in patients with severe sepsis. 4 Inhibitors of 3-hydroxyl-3-methyl coenzyme A (HMGCoA) reductase (statins) are widely used in the treatment of hypercholesterolem...

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Background: In patients with chronic liver disease (CLD), glycated haemoglobin (HbA 1C ) levels have been shown to be apparently lower than real values, whereas serum glycated albumin (GA) levels are apparently higher. The present study was aimed to examine whether both glycaemic indices are influenced by hepatic function. Methods: Subjects consisted of 82 patients with CLD. Various indicators for hepatic function as well as HbA 1C and GA were also measured. Estimated HbA 1C values were calculated from the mean plasma glucose levels. Two hundred and two type 2 diabetic patients without CLD were studied as controls. Results: Although GA was strongly correlated with HbA 1C in patients with CLD as well as diabetic patients, GA levels in patients with CLD were relatively higher than those in diabetic patients. In patients with estimated HbA 1C 5.8%, GA levels significantly increased but HbA 1C levels decreased as a function of decreasing hepaplastin test (HPT). The ratio of GA/HbA 1C (G/H ratio) increased as a function of decreasing HPT. In patients with estimated HbA 1C .5.8%, in contrast, GA levels were independent of HPT levels. In the patients with CLD, GA and HbA 1C were associated with mean plasma glucose levels and some indicators for hepatic function. The multivariate analysis revealed a significant association of G/H ratio with HPT, cholinesterase and direct bilirubin. The G/H ratio was not associated with the mean plasma glucose but with HPT and cholinesterase levels. Conclusions: The G/H ratio correlates with hepatic function but not with plasma glucose levels. Therefore, CLD should be suspected for diabetic patients with an elevated G/H ratio.

Background-Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-␥ on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages. Methods and Results-THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN-␥ was added to the medium, and expression of the VLDL receptor was determined. 125 I-␤-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-␥ inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-␥ receptor mRNA increased during differentiation to macrophages.125 I-␤-VLDL degradation study and oil red O staining showed that IFN-␥ significantly inhibited foam cell formation after the uptake of ␤-VLDL. LDL receptor-related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN-␥ also inhibited VLDL receptor expression and foam cell formation by ␤-VLDL. Conclusions-VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN-␥ inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.

Aims/Introduction:  The aim of the present study was to assess the independent predictors of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients.Materials and Methods:  Data were retrieved from the medical records of 151 type 2 diabetic patients who had been taking sitagliptin 25 or 50 mg once daily for inadequate glycemic control for at least 12 weeks, with or without other oral hypoglycemic agents. Spearman’s rank correlation coefficients were calculated to investigate correlations between two independent continuous variables. Multiple stepwise regression analysis was used to identify independent predictors of reductions in HbA1c levels after 12 weeks of sitagliptin treatment (ΔHbA1c).Results:  In all patients combined, Spearman’s rank correlation coefficients showed that ΔHbA1c was significantly correlated with baseline HbA1c alone (r = 0.371, P < 0.0001). However, multiple linear regression analysis among all patients using baseline variables revealed that the independent factors contributing to ΔHbA1c, in order of importance, were method of prescribing (P < 0.0001), baseline HbA1c (P < 0.0001), body mass index (BMI; P = 0.004), and duration of diabetes (P = 0.024).Conclusions:  Our analysis may provide novel evidence that increased BMI contributes, in part, to attenuation of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients. Analysis of a larger population over a longer period of time is warranted to confirm these findings. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00156.x, 2011)