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...

Background-The delayed release of serum cardiac markers such as creatine kinase isoenzyme MB and equivocal early electrocardiographic changes have hampered a diagnosis of acute myocardial infarction (AMI) in the early phase after its onset. Therefore, a reliable serum biochemical marker for the diagnosis of AMI in the very early phase is desirable. Methods and Results-Serum samples were collected from the patients with AMI, unstable angina pectoris, stable angina pectoris, and other diseases. Levels of serum deoxyribonuclease I (DNase I) activity in the patients were determined. An abrupt elevation of serum DNase I activity was observed within approximately 3 hours of the onset of symptoms in patients with AMI, with significantly higher activity levels (21.7Ϯ5.10 U/L) in this group compared with the other groups with unstable angina pectoris (10.4Ϯ4.41 U/L), angina pectoris (10.8Ϯ3.70 U/L), and other diseases (9.22Ϯ4.16 U/L). Levels of the DNase I activity in serum then exhibited a marked time-dependent decline within 12 hours and had returned to basal levels within 24 hours. Conclusions-We suggest that serum DNase I activity could be used as a new diagnostic marker for the early detection of AMI. Key Words: myocardial infarction Ⅲ enzymes Ⅲ diagnosis I n patients with acute myocardial infarction (AMI), the infarct size is an important determinant of both mortality and morbidity. 1 When revascularization and thrombolytic therapies are initiated rapidly, there is a greater potential for reduction in the infarct size. The release of cardiac proteins from injured cardiac tissue into plasma has been used as a diagnostic marker for the exclusion or confirmation of AMI. 2 However, it is often difficult to make a diagnosis of AMI in the very early phase, ie, within 3 hours of onset. This is partly due to a delay in the appearance in the serum of the biochemical markers specific for myocardial damage. 2,3 Deoxyribonuclease I (DNase I, EC 3.1.21.1), one of the well-known enzymes, was the first enzyme to be recognized as specific for DNA. 4 One of its proposed roles is DNA breakdown during apoptosis. 5 DNase I has been detected in human myocardium, and it has been reported that the activity level increases in heart failure due to idiopathic dilated cardiomyopathy. 6 However, the association between serum DNase I activity level and coronary heart disease (CHD) has not yet been clarified. In the present study, we assessed the serum DNase I activity in patients with AMI and related CHD and found that there is a specific elevation of serum DNase I activity in the very early stages of AMI. Methods Patients and Sample CollectionWe assessed 53 consecutive Japanese patients with AMI admitted to our hospitals between September 2002 and May 2003. The clinical diagnosis of AMI and unstable angina pectoris (UAP) was made according to the European Society of Cardiology/American College of Cardiology Committee criteria. 7 The mean lapse time between the onset of symptoms and hospital admission was 10.7Ϯ13.8 hours. Emergent coronary ang...

Mineralocorticoid receptors (MRs) have been identified in the human cardiovascular tissues. We determined MR expression in the failing heart to clarify the mechanism of action of aldosterone antagonist in the treatment of congestive heart failure. MR protein and MR mRNA content were detected by immunohistochemical staining and in situ hybridization in the cardiac tissues. Immunohistochemical staining of the receptor, as well as in situ hybridization of MR mRNA, was dense in cardiomyocytes of the failing left ventricle as compared with the controls. The staining ratio of the cytoplasm to the interstitium showed that MRs were located mainly in the cytoplasm. The cytoplasm to the interstitium in the failing left ventricle was 1.53+/-0.13, which was significantly higher than that of the controls 1.25+/-0.19 (p<0.05). These findings suggest that the efficacy of aldosterone antagonists in treating congestive heart failure may be in part through blocking the MRs, which are upregulated in the failing heart.

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