Cover to Volume 3

The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth

The influence of implantation techniques on lesion oriented-outcomes in Absorb BVS and Xience EES lesions treated in routine clinical practice at complete three year follow-up: AIDA trial QCA substudy

It has been hypothesized that dedicated optimized Absorb BVS implantation techniques might mitigate the risk of adverse events such as target vessel

Vitronectin and plasminogen activator inhibitor 1 protect against restenosis in a murine model

Plasminogen activator inhibitor 1 (PAI-1) is associated with atherosclerosis and restenosis. However, the detailed role of this serine protease inhibitor in atherogenesis is not well understood. PAI-1 is best known for inhibition of the plasminogen activators (PAs). PAs convert plasminogen into plasmin, which can degrade extracellular matrix components in tissue to facilitate cell migration. In addition, PAI-1 coupled to vitronectin (VN) can form a ternary complex with thrombin, thereby inhibiting thrombin activity. This may be relevant in the vessel wall, since in vitro thrombin is a mitogenic factor for smooth muscle cells (SMCs). Furthermore, it has been established that PAI-1 is involved in adhesion of cells. Each of these different processes plays a role in atherogenesis. Our main focus is on the interaction between PAI-1, VN and thrombin. We already demonstrated that VN, active PAI-1 and active thrombin are present and colocalize in human atherosclerotic plaques. Consequently, our hypothesis is that PAI-1 and its cofactor VN can protect against SMC proliferation in the vessel wall through inhibition of thrombin. Using the murine carotid artery ligation model for restenosis we tested this proposal. Complete ligation of the left common carotid artery near the distal bifurcation results in a SMC-rich neointima. In our study we performed ligation experiments in PAI-1 -'", VN"'" and wild-type mice to determine differences in neointima formation. We demonstrate that VN-'- and PAI1 J- mice display enhanced neointima formation upon carotid artery ligation, compared to wild-type mice. The neointima/media ratio increased 5-fold, from 0.4 +/- 0.3 ( = 4) to 2.0 +/- 0.7 ( = 5) in the VN-'" mice. In the PAI-1"'- mice the ratio was augmented 7-fold, from 0.4 +/- 0.2 ( = 5) to 2.8 +/- 0.3 (n = 4). In addition, the length of the lesion in VN-'- and PAI1-'- mice was twice that of the wild-type mice. These observations are in agreement with our hypothesis that increased neointima formation in the VN-/- and PAI-1-/- mice may be partially due to lack of thrombin inhibition in these mice. Therefore, VN and PAI-1 are thought to have a protective function in restenosis

Degradation of the endothelial glycocalyx is associated with chylomicron leakage in mouse cremaster muscle microcirculation

A thick endothelial glycocalyx contributes to the barrier function of vascular endothelium in macro- and microcirculation. We hypothesised in the current study that diet-induced hyperlipidaemia perturbs the glycocalyx, resulting in decreased dimensions of this layer and increased transendothelial lipoprotein leakage in capillaries. Glycocalyx thickness was measured in mouse cremaster muscle capillaries by intravital microscopy from the distance between flowing red blood cells and the endothelial surface. In control C57BL/6 mice on standard chow, glycocalyx thickness measured 0.58 +/- 0.01 (mean +/- SEM) mu m, and no lipoproteins were observed in the tissue. After three months administration of an either mild or severe high-fat / high-cholesterol diet (HFC) to C57BL/6 and ApoE3-Leiden mice, circulating large lipoproteins appeared into the subendothelial space in an increasing proportion of cremaster capillaries, and these capillaries displayed reduced glycocalyx dimensions of 0.40 +/- 0.02 and 0.30 +/- 0.01 mu m (C57BL/6 mice), and 0.37 +/- 0.01 and 0.28 +/- 0.01 mu m (ApoE3-Leiden mice), after the mild and severe HFC diet, respectively. The chylomicron nature of the accumulated lipoproteins was confirmed by observations of subendothelial deposition of Dil-labeled chylomicrons in capillaries after inducing acute glycocalyx degradation by heparitinase in normolipidaemic C57BL/6 mice. It is concluded that while under control conditions the endothelial glycocalyx contributes to the vascular barrier against trans-vascular lipoprotein leakage in the microcirculation, diet-induced hyperlipidaemia reduces the thickness of the glycocalyx, thereby facilitating leakage of chylomicrons across the capillary wal

TCT-68 One Year Clinical Outcomes in Patients with Insulin-Treated Diabetes Mellitus and Non-Insulin-Treated Diabetes Mellitus Compared to Non-Diabetics after Deployment of the Abluminal Sirolimus Coated Bio-Engineered (COMBO) Stent in an All-Comers Registry

Item does not contain fulltex

Proteasome inhibitors enhance endothelial thrombomodulin expression via induction of Krüppel-like transcription factors

OBJECTIVE: Impairment of the thrombomodulin-protein C anticoagulant pathway has been implicated in pathological thrombosis associated with malignancy. Patients who receive proteasome inhibitors as part of their chemotherapeutic regimen appear to be at decreased risk for thromboembolic events. We investigated the effects of proteasome inhibitors on endothelial thrombomodulin expression and function. METHODS AND RESULTS: Proteasome inhibitors as a class markedly induced the expression of thrombomodulin and enhanced the protein C activating capacity of endothelial cells. Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. These effects were confirmed in vivo, where systemic administration of a proteasome inhibitor enhanced thrombomodulin expression that was paralleled by changes in the expression of KLF2 and KLF4. CONCLUSIONS: These findings identify a novel mechanism of action of proteasome inhibitors that may help to explain their clinically observed thromboprotective effect

TCT-470 Two Year Clinical Results after Deployment of the Abluminal Sirolimus Coated Bio-Engineered (COMBO) Stent in a Thousand Patient All-Comers Registry

Item does not contain fulltex