tbuckley/cabot-search huggingface dataset:
Abstract 5119: Von Willebrand Factor is Expressed Differently in Pathological Angiogenesis Models and Potentially Mediates Angiogenesis
Authors: Yi Xie, Juhua Chen
Journal: Circulation (2009)

The objectives of this study were to assess von Willebrand factor (vWF) expression in different in vivo angiogenesis models, and also to investigate whether vWF plays a role in the regulation of angiogenesis. Basement membrane vWF is widely used as an endothelial cell marker for the analysis of physiological and pathological angiogenesis. In this study, we measured vWF expression in tumor xenografts, ischemic muscle, wound skin and matrigel implants. CD31 antibody, another routinely used endothelial cell marker, was used as an internal control. The sections of different tissues were immunofluorescently stained for vWF and CD31. The top five fields with the most microvessels in each section were acquired. The vWF- and CD31-positive vascular areas were quantified using Image-Pro Plus software and the ratios of vWF-/CD31-positive areas were compared. The ratios in normal muscle, skin and liver were 21.66%, 22.75% and 27.59%, respectively. In ischemic muscle and wound skin, the vWF/CD31 ratios were 23.10% and 21.73%, respectively, which were comparable with those in normal tissues. Matrigel implants had the highest ratio of vWF/CD31 (41.61%). However, tumor xenografts had the lowest ratios of vWF/CD31, which were 3.51% and 5.37% in breast cancer and melanoma, respectively. These data suggested that vWF expression is mediated by the micro-environment of distinct pathological processes. They also implied that the decreased expression of vWF in tumor vasculature might be a potential regulator of tumor growth and angiogenesis. We injected melanoma cells subcutaneously into wild type (WT) and vWF-deficient (vWF−/−) mice to examine tumor growth and vascular formation. Interestingly, the weight of tumors grown in vWF−/− mice was four times higher than that in WT counterparts. Importantly, the vascular area in the tumors from vWF−/− mice was significantly larger than that from the WT littermates. Taken together, these data demonstrate that vWF expression is different in distinct pathological angiogenesis models. Therefore, caution should be taken when using vWF as a vascular marker in different pathological angiogenesis models. Moreover, the decreased expression or deficiency of vWF might be implicated in the promotion of angiogenesis. This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5022: The Relationship Between Plasma Pentraxin 3 and Coronary Plaque Morphologies in Patients With Acute Coronary Syndrome
Authors: Shigeki Kimura, Hiroshi Inagaki, Goh Haraguchi, Osamu Inaba, Toru Miyazaki, Tomoyo Sugiyama, Yu Hatano, Shunji Yoshikawa, Hitoshi hachiya, Kenzo Hirao, Mitsuaki Isobe
Journal: Circulation (2009)

Background: Inflammation is a significant factor contributing to atherosclerotic plaque development. Several inflammatory markers have been used to detect high risk patients with acute phase of ischemic heart disease. Recently, the long pentraxin family member, pentraxin 3 (PTX3) has been reported to be a significant predictor for clinical outcome in patients with acute coronary syndrome (ACS). However, the relationship between PTX3 and coronary plaque components has not been fully clarified. We tried to investigate the difference of plaque morphologies on intravascular ultrasound (IVUS) in ACS lesions among with elevating PTX3 or without. Methods: Eighteen target lesions in 18 ACS patients (ST-elevation MI (STEMI); 17 patients, non-STEMI; 1 patients), who underwent preintervention virtual histology (VH) - IVUS, were investigated. PTX3 was collected from all patients before percutaneous coronary intervention. The lesions were divided into two groups; group A with PTX3 ≥ 4ng/ml and group B with PTX3&lt;4ng/ml. The differences of plaque morphologies on VH-IVUS were evaluated between the two groups. The presence of thin-cap fibroatheromas (TCFA), defined as a necrotic core ≥ 10% of plaque area at the minimal lumen area site without overlying fibrous tissue in the presence of &gt;40% plaque burden characteristic. The presence of echo signal attenuation (EA) on IVUS, which recently has been reported to be related with no-reflow after PCI, was defined as atherosclerotic plaque showing ultrasound signal attenuation without very high intensity echo reflectors. Results: An elevation of PTX3 (≥4.0ng/ml) was detected in 10 lesions (55.6%). Lesion vessel area (20.1±3.3mm 2 vs. 14.8±4.9mm 2 , p&lt;0.01) and plaque volume (312±118mm 3 vs. 200±93mm 3 , P&lt;0.05) was significantly greater in group A than group B. Remodeling index was not significant but tended to be higher in lesion with group A than group B (1.19±0.19 vs. 1.06±0.17, p=0.13). The frequency of EA (60.0% vs. 0.0%, p&lt;0.05) and TCFA (50.0% vs. 0 %, p&lt;0.05) was significantly higher in lesions with group A than group B. Conclusions: In ACS lesions, pentraxin 3 might be a significant predictor for the presence of large amount of unstable and vulnerable plaque compositions, which might lead to a poor clinical outcome after PCI.
Abstract 4183: Gender Difference in the Relationship Between Socioeconomic Deprivation and Fatal Compared to Non-fatal Myocardial Infarction
Authors: Pardeep Jhund, Kate Macintyre, John McMurray
Journal: Circulation (2006)

Introduction: Although socioeconomic deprivation (SED) has been identified as an important risk factor for myocardial infarction (MI), it is not clear whether it predicts outcome after adjustment for traditional risk factors. The relative importance of SED as a predictor of fatal versus non-fatal outcomes and in men versus women is also uncertain. Hypothesis: We hypothesized that SED is an independent predictor of both first hospitalization for MI and MI death (and equally so in men and women). Methods: We examined outcomes in 15,378 men and women initially surveyed between 1972–76 in Renfrew and Paisley, Scotland, and followed until 3/31/2004. Hazards ratios (HR) for a first admission with a MI (as principal diagnosis) and death from MI were calculated using Cox Regression. All analyses were adjusted for age, body mass index, systolic and diastolic blood pressure, cholesterol, smoking, ECG ischemia, and a history of diabetes, angina or stroke. Deprivation was defined using the seven category Carstairs deprivation index. Deprivation categories (depcat) 6 and 7 (the most deprived depcats) were combined to increase power due to small numbers of individuals in group 7. Log rank tests were used to compare the overall trend across depcats. Results: During &gt;=28 years follow-up, 1873 men and women had a first MI hospitalization and 2370 a MI death. Compared to the most affluent (depcat 1), the risk of MI death in men and women combined in depcat 6/7 was 37% higher (hazard ratio (HR) 1.37 (P=0.001)), trend P&lt;0.0001. The HR for men alone in depcat 6/7 versus depcat 1 was 1.35 (P=0.018) and similarly 1.38 for women alone (P=0.027). For men and women in depcat 6/7 (compared to depcat 1), the HR for a first MI hospitalization was 1.34 (P= 0.007), P&lt;0.0001. The HR was 1.1 for men (P=0.5) and 1.74 for women (P=0.002). Conclusion: SED is associated with an increased risk of MI death which is of similar magnitude in men and women, even after accounting for “traditional” risk factors. By contrast, SED is associated with a smaller risk of 1st hospitalization for MI in men than women. This explanation for this gender difference is uncertain but may represent a differential effect of SED on survival to hospital admission in men and women.
Abstract 5069: Loss of MHC Class II Transactivator Causes Abdominal Aortic Aneurysm
Authors: Koichi Shimizu, Yukiko Asami, Eduardo J Folco, Hoi Ching Tang, Rica Shubiki, Peter Libby
Journal: Circulation (2009)

Th1 and/or Th2 cytokines produced by inflammatory cells may influence the outcome of arterial inflammation. Indeed, Th2 type cytokines predominate in human abdominal aortic aneurysm (AAA) lesions, while cells in stenotic atherosclerotic lesions preferentially express Th1 cytokines. The major histocompatibility complex (MHC) class II transactivator (C2ta) is a transcriptional co-activator responsible for IFN γ -inducible MHC class II expression on antigen-presenting cells. C2ta can also modulate IL-4 and MMPs. This study tested the hypothesis that C2ta deficiency could induce MMP expression and cause aortic aneurysm formation in atherogenic animals. Results: Real-time quantitative PCR and Western blot demonstrated that human AAA tissues express significantly less C2ta mRNA and lower HLA-DR protein levels than the atherosclerotic aortic tissue. In addition, human AAA tissues express significantly elevated MMP9 and MMP12 protein levels. 12-week-old male ApoE−/− and ApoE/C2ta−/− mice consumed a 1.25% cholesterol diet up to 8M. The abdominal aortic diameter below the renal artery branches of ApoE/C2ta−/− mice increased at 8M compared to the ApoE−/− mice (1.68±0.28 vs. 0.90±0.10 mm, mean± SD, p &lt; 0.0001). The morphological analysis of the ApoE/C2ta−/− mice fed with 8M atherogenic diet showed fragmentation of the medial elastic lamellae and expanded luminal area, characterizing aortic aneurysm. ApoE/C2ta−/− mice had higher plasma levels of IL-4 and IL-10 (4.9±3.0 and 114.2±75.5 ng/mL, mean±SD, n=10) than ApoE−/− mice (1.9±2.2, p=0.0057; and 29.9±24.1 ng/mL, p=0.0062, respectively) after 8M on an atherogenic diet. Western blot and zymography showed significantly higher expression and activity of MMP9 and MMP12 in the aortic lesions of the ApoE/c2ta−/− compared to those of the ApoE−/− mice at 6M high-cholesterol diet. The aortic diameter of the triple deficient animals of ApoE/C2ta/MMP9 −/− and ApoE/C2ta/MMP12 −/− did not increase even after 8M on an atherogenic diet (0.76±0.21 mm, mean± SD, n=10; 0.68±0.10 mm, n=10, p &lt;0.0001 vs. ApoE/C2ta−/−). Conclusion: This study illustrates a novel mechanism for Th2 dominant cytokine milieu in a subset of patients with aortic atherosclerosis and how impaired signaling of C2ta and IFN- γ promote AAA formation. This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5466: Nuclear Receptor Nurr1 in Vascular Smooth Muscle Cells is Protective in In-stent Restenosis
Authors: Peter I Bonta, Thijs W Pols, Claudia M van Tiel, Ilze Bot, Robbert de Winter, Hans Pannekoek, Erik A Biessen, Carlie J de Vries
Journal: Circulation (2009)

Introduction Coronary atherosclerosis is treated by percutaneous coronary intervention (PCI) in combination with stent placement. The major drawback of this intervention is (in-stent) restenosis, which is characterized by activation and excessive proliferation of smooth muscle cells (SMCs). In previous studies we have shown that nuclear receptor Nurr1 inhibits the inflammatory response of macrophages and reduces lipid loading of these cells. In this study we investigated nuclear receptor Nurr1 in SMCs in human and experimental vascular restenosis. Methods and results In a prospective cohort of 601 patients undergoing PCI including stent-placement, we report a strong association of Nurr1 haplotypes with angio-graphic and clinical in-stent restenosis risk (Hazard ratio (HR) 3.1; 95%CI:1.9–5.1 and HR 3.4; 95%CI 1.6–7.1, respectively). Furthermore, Nurr1 is expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor (TNF)- α -mediated activation. Lentivirus-mediated gain and loss of function experiments in SMCs demonstrated that overexpression of Nurr1 inhibited proliferation, consistent with increased expression of the key cell-cycle inhibitor p27 Kip1 , whereas Nurr1 silencing enhanced SMC growth. The TNF α -induced pro-inflammatory response of SMCs is inhibited by Nurr1 as reflected by reduced interleukin-1 β , TNF α and monocyte chemo-attractant protein-1 expression. In subsequent mouse experiments, Nurr1 was locally expressed in the carotid artery of ApoE−/− mice after wire-induced injury, and we revealed that Nurr1 inhibits SMC-rich lesion formation. In line with this observation, silencing of murine Nurr1 in the vessel wall increased lesion formation. Conclusion Nurr1 haplotypes associate with human in-stent restenosis risk and Nurr1 is expressed in in-stent restenosis. In addition to the anti-inflammatory function of Nurr1 in macrophages, we show that Nurr1 inhibits proliferation and inflammatory responses in SMCs, which explains inhibition of SMC-rich lesion formation in mice. Since small-molecule drugs that enhance the activity of Nurr1 have been identified, we propose this nuclear receptor Nurr1 as an attractive novel target for (local) intervention in restenosis.
Abstract 571: Triggered Delayed Afterdepolarizations induce Multifocal and Bidirectional Ventricular Tachycardia in a Model of Andersen-Tawil (Long QT 7) syndrome
Authors: Hiroshi Morita, Douglas P Zipes, Shiho T Morita, John Lopshire, Jiashin Wu
Journal: Circulation (2006)

( Introduction ) Andersen syndrome (AS) is a rare channelopathy induced by the mutation of KCNJ2, which encodes the inward rectifier potassium current (IK1) Kir2.1. ECG shows prolonged QT interval, large U waves and frequent multifocal ventricular tachycardia (VT), which is often bidirectional VT. Torsades de pointes (tdp) is rare. We investigated the mechanism of VT in AS using cesium chloride (Cs), an IK1 blocker, in canine ventricular tissues. ( Method and Results ) Using an optical mapping system, we mapped action potentials (APs) at 256 sites on the cut-exposed transmural surfaces of 16 canine left ventricular preparations. Tissues were perfused by Tyrode solution having normal potassium (K = 4.7 mEq, n = 7) or low K concentration (K = 2.5 mEq, n = 9). Pacing (cycle length, CL = 4000 - 400 ms) was performed in control, Cs (5–10 mM) and Cs with isoproterenol (Cs+ISP, 0.15 uM) preparations. Cs prolonged the QT interval and AP duration (APD) at both K concentrations, but more so in low K Tyrode (normal K: endocardial APD control 254 ± 17, Cs 385 ± 16 ms, p&lt;0.01; low K: endocardial APD control 293 ± 19, Cs 459 ± 22 ms, p&lt;0.01). Midmyocardial APDs did not show excessive APD prolongation (i.e., no M cell behavior). Rapid pacing (CL 1000 - 400 ms) induced delayed afterdepolarizations (DAD) at both K concentrations with Cs (occurrence of DAD: low K 100%, Normal K 11%) and ISP increased DAD prevalence in normal K (Normal K 67%). DADs often appeared in mid wall and endocardium sites and resulted in large U waves in 11 tissues. Repetitive triggered activity from DADs induced multifocal VT at both K concentrations with Cs+ISP (VT occurrence: low K 100%, normal K 56%). Migration of DAD-VT foci within transmural tissues from mid to endocardium resulted multifocal VT. Alternating discharge of 2 DAD foci resulted in bidirectional VT in 4 tissues with low K. VT was sustained and had multiple foci in low K Tyrode compared to normal K Tyrode (VT duration: low K 10.9 ± 7.2, normal K 1.3 ± 1.5 min, p&lt;0.01; number of foci: low K 5.2 ± 2.0, normal K 1.9 ± 1.5, p&lt;0.01). Early afterdepolarizations and tdp did not occur in this model. Verapamil abolished DADs in all tissues. ( Conclusion ) IK1 blockade mimicking AS induced long QT and manifest U waves. Migration of multiple DAD-VT foci induced multifocal and bidirectional VT.
Occult Left Ventricular Mass Presenting as a Wide-Complex Tachycardia in a 47 Year Old Female
Authors: Brian C Kolski
Journal: Circulation (2009)

Abstract #3083 Brian C Kolski, William D Ryan, Ahmed Shabaik, Gregory K Feld, Andrew Kahn, Univ of California, San Diego, San Diego, CA Brian C Kolski, 2009 Finalist and Presenting Author
Abstract 5068: Interaction Between CD36 and Oxidized LDL Induces Loss of Cell Polarity and Inhibits Macrophage Migration: A Mechanism of Macrophage Trapping
Authors: Young M Park, Judith A Drazba, Maria Febbraio, Roy L Silverstein
Journal: Circulation (2009)

Trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherosclerosis. Previous studies from other laboratories showed that regressed atherosclerotic lesions were characterized by emigration of lipid-laden macrophages. CD36, a class B scavenger receptor expressed on macrophages is a pathogenic factor for foam cell formation and atherosclerosis. We recently showed that oxidized LDL (oxLDL) modulates macrophage cytoskeletal signaling via CD36, inhibiting migration and thus potentially contributing to intimal trapping. We now hypothesize that oxLDL-CD36 inhibition of migration is the result of specific intracellular signals that regulate cell polarity. Methods/Results: Live cell imaging of murine peritoneal macrophages showed that oxLDL, but not native LDL, induced loss of cell polarity. Macrophages from cd36 null mice did not show this effect. Similarly, macrophages from mice null for Vav, a guanine nucleotide exchange factor recently shown to be a downstream effector of CD36 signaling, did not show oxLDL-induced loss of polarity. Macrophage migration velocity and dynamic movement of macrophage membrane were decreased by oxLDL in wild type macrophages by 85% and 86% respectively, but not in cd36 null or vav null macrophages. These findings appear to be related to activity of myosin II, a recently suggested cell polarity determinant. Western blots for phosphorylated myosin regulatory light chain (MRLC) showed that oxLDL, but not native LDL, induced de-phosphorylation of MRLC by 80%. Enzyme linked immunosorbent assays for GTP-bound Rac, a regulator of MRLC phosphorylation, showed that macrophage Rac-GTPase activity was increased 2.6 fold by oxLDL. These findings were not observed in macrophages from cd36 null or vav null mice. 6-thio-GTP, a Rac-GTPase inhibitor that inhibits binding of Vav to Rac1 abrogated the effect of oxLDL on MRLC dephosphorylation. Conclusion: OxLDL interaction with CD36 inhibited macrophage migration and caused loss of cell polarity. The mechanism by which this occurs is via Vav-dependent activation of Rac-GTPase and dephosphorylation of MRLC. Activation of this pathway in the vessel wall may induce trapping of macrophages in the arterial intima and promote atherosclerosis.
Abstract 5122: Hepatocyte Growth Factor Attenuates Renal Fibrosis Through Myofibroblasts Anoikis Induced by FAK/MMP Activaton
Authors: Kazuma Iekushi, Yoshiaki Taniyama, Junya Azuma, Fumihiro Sanada, Norio Dosaka, Keita Okayama, Hiroshi Kusunoki, Toyohiko Yokoi, Hiromi Rakugi, Ryuichi Moroshita
Journal: Circulation (2009)

Progression of chronic kidney disease (CKD) is characterized by the accumulation of extracellular matrix. Especially, α -SMA positive myofibroblasts, which produce high amounts of TGF- β 1, plays a key role in interstitial fibrosis. Previous studies demonstrated hepatocyte growth factor (HGF) improved kidney fibrosis, whereas mechanisms of HGF on prevention of renal fibrosis have not been fully understood. Since HGF may contribute to myofibroblasts apoptosis/anoikis, we tested whether HGF increased MMP expressions and contributed to myofibroblasts apoptosis/anoikis. When human mesangial cells were treated with TGF- β 1, cells phenotypically changed to myofibroblasts, and this was associated with up-regulation of c-Met/HGF receptor (P&lt;0.05). HGF significantly increased MMP-2/-9 expression (P&lt;0.05) of myofibroblasts. Furthermore, HGF increased phosphorylation of Tyr925 FAK, suggesting the role of MMPs and FAK on HGF induced apoptosis. Indeed, when GM6001(GM;MMP inhibitor) or FAK siRNA were treated in combination with HGF, HGF-mediated myofibroblast apoptosis was significantly inhibited (HGF alone; 8.1±0.2%, HGF+GM; 3.4±0.2%, HGF+FAK siRNA; 3.6±0.3%, P&lt;0.05). Next, we tested the anti-fibrotic effect of HGF using cardiac specific HGF over-expressing mice (HGF-Tg). Angiotensin II (Ang II) infusion induced renal fibrosis in litter mates control, while it was significantly inhibited in HGF-Tg accompanied with the significant depletion of interstitial myofibroblasts (P&lt;0.05). TGF β -1, collagen type I and IV mRNA in HGF-Tg were significantly reduced compared to control (qPCR; P&lt;0.05). Consistent with the in vitro studies, HGF-Tg significantly increased MMP-2/-9 expression (P&lt;0.05). TUNEL and α -SMA double-positive cells induced by Ang II, which represents myofibroblasts apoptosis, was reduced in HGF-Tg compared to control (3.7±0.3 vs 1.7±0.4%, P&lt;0.05). Furthermore, GM6001 injections in HGF-Tg with Ang II cancelled the anti-fibrotic effects of HGF accompanied with the depletion of myofibroblasts. In summary, increased activities of FAK-MMPs underlie the major mechanism of HGF mediated anoikis/apoptosis of myofibroblasts. Activation of MMPs by HGF might be a target to attenuate the progression of renal fibrosis in CKD.
Abstract 5042: Interferon-gamma Induced Adipose Inflammation Linked to the Impairment of Vascular Function in Type 2 Diabetic Mice
Authors: Hanrui Zhang, Cuihua Zhang
Journal: Circulation (2009)

Interferon-gamma (IFN) is the hallmark cytokine of Th1 cells and plays a major role in immuno-mediated inflammation in type 1 diabetes. However, the role of IFN in initiating adipose inflammation and subsequent vascular dysfunction in type 2 diabetes remains to be determined. Accordingly, we hypothesized that IFN induces inflammatory cell infiltration and chemoattractant gene expression in mesenteric adipose tissue (MAT) and impairs vascular function of small mesenteric arteries (MA) of type 2 diabetic mice. To test this, we studied MAT inflammation, and vascular function of MA in control mice (m Lepr db ), diabetic mice (Lepr db ), m Lepr db treated with IFN, Lepr db treated with anti-IFN or anti-monocyte chemoattractant protein (MCP)-1. Acetylcholine (ACh)-induced vasodilation was impaired in Lepr db vs. m Lepr db , but sodium nitroprusside (SNP)-induced vasodilation was comparable. Both anti-IFN and anti-MCP-1 improved endothelial function in Lepr db , while IFN induced impaired vascular function in m Lepr db . Mesenteric bed weight and MAT adipocyte size were greatly elevated (P&lt;0.05) in Lepr db vs. m Lepr db . Immunohistochemical staining results revealed that CD3-positve T-lymphocytes, F4/80 and Mac-3 positive macrophage infiltration into MAT was markedly increased in Lepr db and IFN-treated m Lepr db . It showed reduced MAT macrophages infiltration in Lepr db treated with anti-IFN vs. Lepr db . Interestingly, Mac-3 positive macrophage infiltration into the adventitia of small mesenteric arteries was significantly increased in Lepr db and IFN-treated m Lepr db , suggesting the possible crosstalk between adipose inflammation and vascular dysfunction. Western blotting results showed that anti-IFN decreased MAT IFN and MCP-1 protein expression in Lepr db , while IFN and MCP-1 expression was elevated in IFN-treated m Lepr db . Anti-MCP-1 treatment only decreased MCP-1 expression in Lepr db without affecting IFN levels, indicating that IFN may act as an initiator of MAT inflammation and chemoattractant gene expression. These results suggest a role for IFN in the regulation of visceral adipose inflammatory response and vascular dysfunction in type 2 diabetes. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).