Efficient luminescent properties and cation recognition ability of heavy group 13 element complexes of N2O2- and N2O4-type dipyrrins.

The first mononuclear 1 : 1 complexes of heavy group 13 elements (Ga and In) and N2O2/N2O4-type dipyrrins were synthesized and characterized. The N2O2-type complexes showed efficient luminescent properties even in polar solvents. The N2O4-type complexes exhibited fluorometric responses to alkaline earth metal ions.

Increased vascular wall thrombogenicity combined with reduced blood flow promotes occlusive thrombus formation in rabbit femoral artery.

OBJECTIVE: Plaque disruption does not always result in complete thrombotic occlusion. The mechanism of arterial thrombus propagation remains unclear. METHODS AND RESULTS: We studied how vascular wall thrombogenicity and blood flow reduction affect thrombus propagation using a rabbit model of single and repeated balloon injury. After balloon injury of the normal femoral artery, the blood flow was reduced to 50%, 25%, or 10% (n=5). Small mural thrombi composed of aggregated platelets were produced, but no occlusive thrombi developed in any flow reduction. Three weeks after the first balloon injury, neointima with tissue factor expression and increased procoagulant activity was developed. Balloon injury of the neointima with the same blood flow reduction (n=5) induced fibrin-rich thrombus formation. Additionally, injury with flow reduced to 25% and 10% promoted thrombus propagation resulting in vessel occlusion within 160+/-18 and 71+/-17 seconds, respectively. An injection of anti-von Willebrand factor (vWF) monoclonal antibody (AJW200; 1.0 mg/kg) prevented occlusive thrombus formation. CONCLUSIONS: Increased vascular wall thrombogenicity together with a substantial blood flow reduction is crucial for occlusive thrombus formation, and vWF plays an important role in thrombus propagation. Reduced blood flow at plaque disruption sites might contribute to thrombus propagation leading to acute coronary syndromes.

Contribution of von Willebrand factor to thrombus formation on neointima of rabbit stenotic iliac artery under high blood-flow velocity.

OBJECTIVE: It has become clear that von Willebrand factor (vWF) plays important roles in platelet adhesion and aggregation under high blood-flow velocity conditions observed in stenotic atherosclerotic arteries. However, its roles in thrombus formation in vivo on diseased arteries have not been fully understood. We examined the contribution of vWF to thrombus formation and subsequent intimal growth by using a repeated balloon-injury model in rabbits. METHODS AND RESULTS: Rabbit iliac arteries 4 weeks after a first balloon injury showed 37% luminal stenosis by neointimal growth, and blood velocity increased by 2.1 times compared with that of uninjured arteries. The second balloon injury induced fibrin-rich thrombus formation on the injured neointima. Intravenous administration of a monoclonal antibody against vWF (AJW200, 1.0 mg/kg body weight) remarkably prevented botrocetin-induced platelet aggregation ex vivo for 2 days; moreover, thrombus formation, cell proliferation, and subsequent neointimal growth were significantly reduced at 30 minutes, 5 days, and 4 weeks, respectively, after the second balloon injury. CONCLUSIONS: These results indicate that vWF plays a potent role in fibrin-rich thrombus formation on the neointima under high blood-flow velocity conditions. Inhibition of plasma vWF activity might be effective for the reduction of thrombus formation and/or subsequent neointimal development after coronary interventions.

Immunohistological localization and possible functions of adrenomedullin.

In this short review, we describe the distribution of adrenomedullin (AM)-immunoreactive cells in human tissues and their related biological properties, focusing on the blood coagulation and mucosal defense systems. AM is widely distributed in human tissues, especially in cardiovascular and endocrine tissues. Within vessels, AM has been immunohistochemically detected in vascular smooth muscle cells (SMCs) and endothelial cells (ECs). In atherosclerotic lesions, the peptide is present not only in these cells, but also in macrophages, and the most intense AM immunoreactivity is detected in macrophages located in shoulder lesions of atheromatous plaque, which are considered to be rupture-prone regions. AM inhibits tissue factor production, and augments the production and release of tissue factor pathway inhibitor from aortic ECs. AM also induces the release of antithrombin and urokinase-type plasminogen activator from ECs. Taken together, these antithrombotic properties of the peptide are expected to play an important role in the maintenance of blood circulation. Furthermore, AM immunoreactivity is observed in mucosal and glandular epithelia of the gastrointestinal, respiratory and reproductive systems. AM and the proadrenomedullin N-terminal 20 peptide (PAMP) show strong antibacterial activity against Escherichia coli. In addition, AM is also present in the auditory system. These lines of evidence suggest that AM and its related peptides not only play a role in vasodilatation, but also exhibit multiple biological activities in mammals.

Adrenomedullin augments the release and production of tissue factor pathway inhibitor in human aortic endothelial cells.

OBJECTIVES: Adrenomedullin (AM) is a hypotensive and vasodilative peptide. It has been reported that AM plays several biological roles in cardiovascular and endocrine systems, however, effects on the blood coagulation system have not been examined. In this study, we examined its effect on tissue factor pathway inhibitor (TFPI), which is a potent inhibitor of tissue factor/factor VIIa complex-induced coagulation cascade, and is synthesized and constitutively secreted by endothelial cells (ECs). The aim of this study was to elucidate the effects of AM on release and production of TFPI in ECs. METHODS: Cultured human aortic ECs were incubated with AM (10(-14)-10(-6) M), and the antigen levels and activity of the free and total form of TFPI after AM exposure were measured in culture media using ELISA. Furthermore, receptor interaction and cellular signaling of AM were investigated. RESULTS: AM augmented TFPI release and production in a dose-dependent manner. The effect on TFPI production was inhibited by AM receptor antagonist (AM22-52), the monoclonal antibody against C-terminal region of AM, MAPKK inhibitor, and cAMP antagonist. CONCLUSION: These findings indicate that AM might play an important role in the modulation of anticoagulant properties in blood circulation.

Protease-activated receptor 2 (PAR2) mediates vascular smooth muscle cell migration induced by tissue factor/factor VIIa complex.

UNLABELLED: Protease-activated receptor 2 (PAR2) is one of G-protein-coupled receptors able to be activated by trypsin and coagulation factor VIIa. We previously reported that tissue factor/factor VIIa (TF/FVIIa) complex was a strong chemotactic factor for cultured vascular smooth muscle cells (SMCs). The migratory response was dependent on a catalytic activity of FVIIa, and did not involve factor Xa and thrombin generation. In this study, we examined TF/FVIIa-induced SMC migration. METHODS: The contribution of PAR2 to TF/FVIIa-induced vascular SMC migration was investigated using a modified Boyden's chamber method, and the distribution of PARs in the human coronary arteries and cultured SMCs was also examined. RESULTS: Trypsin and PAR2-activating peptide (AP; SLIGKV) stimulated SMC migration in a dose-dependent manner, of which abilities were comparable to those of TF/FVIIa complex and platelet-derived growth factor-BB, but PAR1-AP (TFLLR or SFLLR) or PAR4-AP (AYPGOV) did not elicit the migration. The antisera against PAR2-AP significantly inhibited TF/FVIIa-induced SMC migration, but that of PAR1-AP did not. In immunostaining, both intimal SMCs of the human coronary arteries and cultured SMCs showed positive reaction for PAR2-AP. CONCLUSION: These results suggest that PAR2 in SMCs plays a crucial role in the cell migration induced by TF/FVIIa complex.

Intravascular ultrasound imaging in the assessment of atherosclerotic plaques in rabbit abdominal aorta: comparison with histologic findings.

RATIONALE AND OBJECTIVES: To examine the correlation between the echogenicity and the components of atherosclerotic plaques in rabbit. METHODS: The atherosclerotic plaque formation in the abdominal aortas of hyperlipidemic or normolipidemic rabbits was stimulated by inserting polyethylene tubing. Intravascular ultrasound (30-MHz, 4.5 F catheter) investigation was performed at locations in the vessel. The intravascular ultrasound images of the plaques were evaluated and compared with the histologic findings. RESULTS: Ultrasound images delineated areas showing hyperechoic or hypoechoic ultrasound beams in the plaques. Histologic studies revealed that the hyperechoic areas were closely associated with a dense fibrous extracellular matrix, whereas the hypoechoic areas corresponded to lesions showing a marked accumulation of foamy macrophages or proteoglycan-rich loose myxoid extracellular matrix with smooth muscle cell proliferation. CONCLUSION: A good correlation between ultrasound images and histologic features was observed. These results suggest that intravascular ultrasound imaging could provide useful information for assessing the tissue characteristics of atherosclerotic lesions.

Atheroembolic renal disease: clinical findings of 11 cases.

Atheromatous embolism is a systemic disease resulting from cholesterol crystal embolization in many organs, including the kidneys. To characterize atheroembolic renal disease (AERD), we retrospectively evaluated 11 patients with acute renal failure after vascular surgery, vascular radiology investigations, and anticoagulation at Miyazaki Medical College from 1994 to 2001. The diagnosis of cholesterol atheromatous embolism was confirmed by tissue examination or clinical grounds. The patients were all elderly men (average age of 66.8 years) with a history of hypertension (55%), diabetes mellitus (45%), hyperlipidemia (45%), and coronary artery disease (18%). Seven patients had livedo reticularis, and 4 had blood eosinophilia. Clinically, 7 patients were managed conservatively and 5 of them improved, whereas 4 patients required dialysis and developed chronic renal failure or died. The serum creatinine levels of the improved patients were significantly lower (1.28+/-0.3 mg/dl, p < 0.005) than the non-improved ones (7.70+/-3.6). The number of eosinophils was significantly higher in the improved patients (576+/-295 /ml, p < 0.05) than in the non-improved ones (208+/-206). However, no significant difference was observed in the levels of serum cholesterol and C-reactive protein among these patients. Since the population at risk for AERD is growing, we should recognize this disease as a cause of acute renal failure.