tbuckley/cabot-search huggingface dataset:
Abstract 5308: Role of Vascular Endothelial Growth Factor-A in the Development of Mice CaCl <sub>2</sub> Induced Abdominal Aortic Aneurysm
Authors: Hidehiro Kaneko, Toshihisa Anzai, Toshiyuki Takahashi, Yuichiro Maekawa, Masayuki Shimoda, Koichi Yoshimura, Hiroki Aoki, Hideyuki Shimizu, Yasunori Okada, Ryohei Yozu, Tsutomu Yoshikawa, Satoshi Ogawa
Journal: Circulation (2009)

Background: Abdominal aortic aneurysm (AAA) is histologically characterized by increased angiogenesis, chronic inflammation, and extracellular matrix degradation. We sought to elucidate the role of vascular endothelial growth factor (VEGF)-A, which is a potent angiogenic and proinflammatory factor, in the development of AAA. Methods and Results: We obtained human aortic wall samples (n=10) during surgical repair of AAA. Autopsy samples from normal aortic wall were served as control (n=6). Immunohistochemistry showed increased CD31 positive vessels, VEGF-A expression, and CD68 positive macrophage infiltration in the aortic wall of AAA compared with control samples. Next, we induced AAA in mice by periaortic application of CaCl 2 . Mice were treated with intraperitoneal injection of soluble VEGF-A receptor-1 (sFlt-1) 1mg/g (FLT, n=8) or PBS 1 μ l (CON, n=8) on alternative day and sacrificed 28 days after the operation. Blood pressure, heart rate, and body weight on day 28 were comparable between FLT and CON. Treatment with sFlt-1 significantly reduced aneurismal size (1.7±0.9 vs. 1.3±0.2 mm, p&lt; 0.01) in association with lowering serum VEGF-A level (p&lt; 0.01). Elastica von Gieson staining showed that wavy morphology of the elastic lamellae was destroyed in CON, but was preserved in FLT. Administration of sFlt-1 reduced zymographic active form of matrix metalloproteinase (MMP)-9 abundance and decreased MMP-9 positive cell count in the aortic wall compared with CON (both p&lt;0.05). Immunohistochemistry showed significantly fewer Mac-3 positive monocytes/macrophages, CD31 and VEGF-A positive cells in periaortic tissues in FLT compared with CON (all p&lt;0.05). Aortic wall mRNA expression of MCP-1, TNF-alpha, and TNF-alpha converting enzyme (TACE) in FLT was lower than that in CON (all p&lt; 0.05). Immunoblotting showed decreased expression of p-JNK in FLT compared with CON (p&lt; 0.05). Conclusions: VEGF-A was overexpressed in arterial wall of human AAA and experimental model of AAA. Treatment with sFlt-1 in mice prevented AAA development, in association with reduced neoangiogenesis, MMPs activity, infiltration of inflammatory cells and JNK activity, and preserved ECM structure. These findings suggest a crucial role of VEGF-A in the development of AAA.
Abstract 5420: Suppression of Aldosterone Mediates Left Ventricular Hypertrophy Regression in Patients With Hypertension
Authors: Anne-Catherine Pouleur, Hajime Uno, Margaret Prescott, Akshay Desai, Evan Appelbaum, Valentina Lukashevich, Beverly A Smith, Björn Dahlöf, Scott D Solomon
Journal: Circulation (2009)

Background . Although high circulating aldosterone levels stimulate myocardial fibrosis and left ventricular hypertrophy (LVH), it is less clear whether suppression of aldosterone is associated with LVH regression in hypertensive patients. Methods. The Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial randomized 465 hypertensive overweight subjects to the direct renin inhibitor aliskiren 300mg, losartan 100mg or the combination and followed patients for 9 months. All patients were treated to standard blood pressure targets. LV mass index (LVMI) and LV wall thickness (LVWT) were assessed by cardiac magnetic resonance. A subset of 135 patients with plasma aldosterone (ALDO) measured at baseline and study end was analyzed. Results. At baseline, ALDO correlated poorly with systolic blood pressure (SBP) (r=0.2, p=0.02), LVMI (r=0.18, p=0.03) and LVWT (r=0.22, p=0.01). Mean blood pressure was 144±13/90±9mmHg, mean LVMI was 75±16 g/m 2 , and mean LVWT was 9.8±2.2mm. ALDO was reduced between baseline and end of the study in the aliskiren [244 (202–294) vs. 198 (161–243) pmol/L, p=0.03] and combination groups [209 (169–257) vs. 164 (138–196) pmol/L, p=0.0029], but not in the losartan group [223 (181–275) vs. 235 (199–278) pmol/L, p=0.63] [geometric means (95%CI)]. Reduction in ALDO was associated with regression of LVWT, even after adjustment for SBP reduction, treatment, baseline ALDO and baseline LVWT (p= 0.041). Conclusion . In hypertensive patients with increased LVWT, regression of LVH was associated with suppression of ALDO, independently of the change in SBP, suggesting that ALDO, a known mediator of LVH, may be a particularly important target for suppression.
Abstract 5337: Morphological Characteristics of the Culprit Lesion Correlate With the Angiographic Flow Grade Following Thrombolysis in Myocardial Infarction. An Optical Coherence Tomography Study
Authors: Antonis Karanasos, Konstantinos Toutouzas, Maria Drakopoulou, Andreas Synetos, Maria Riga, Eleftherios Tsiamis, Dimitrios Klettas, Costas Tentolouris, Elli Stefanadi, Christodoulos Stefanadis
Journal: Circulation (2009)

Background: Intravenous thrombolysis fails to restore blood flow in a significant percentage of patients with ST-elevation myocardial infarction (STEMI). It remains unknown, whether certain morphological characteristics of the culprit lesion (CL) can predict the success of thrombolysis. We hypothesized that the thickness of the fibrous cap and the incidence of plaque rupture at the CL, as measured by Optical Coherence Tomography (OCT), may correlate with the outcome of thrombolysis. Methods: We prospectively enrolled 55 consecutive patients with STEMI that were treated with thrombolysis 6 hours from symptom onset. All patients underwent coronary angiography within 24 hours from thrombolysis. We estimated TIMI flow grade and the corrected TIMI frame count (CTFC) for patients with TIMI flow II or III. In target vessels with TIMI flow grade ≤1 aspiration thrombectomy was performed. We then acquired OCT images from the CL. We measured the fibrous cap thickness (FCT) at the thinnest part overlying a lipid pool, the lipid content (in quadrants) and the incidence of plaque rupture, which was defined as the presence of fibrous-cap discontinuity. Results: Of the total study population, 15 patients had TIMI flow 0 or I, 15 had TIMI flow II, and 25 had TIMI flow III. The number of lipid quadrants was greater in patients with TIMI flow 0-I than in patients with TIMI flow II and III (median 4, (range 1) vs. median 3 (range 2) vs. median 2 (range 1), p&lt;0.001). The culprit lesion of the patients with TIMI flow 0 or I was more often characterized by a ruptured plaque compared to those with TIMI flow II and III (n=13 (86.67%) for TIMI 0–1, n=8 (53.33%) for TIMI II and n=6 (24%) for TIMI III, p&lt;0.001). For patients with TIMI 0 and I, minimum FCT was 41±7 μ m, for patients with TIMI II 55±23 μ m and for those with TIMI III 87±26 μ m (p&lt;0.001). In patients with TIMI flow II or III, a correlation was found between CTFC and the minimal cap thickness (r=−0.423, p=0.006). Conclusion: In patients with STEMI, TIMI flow III following thrombolysis is associated with greater fibrous cap thickness, reduced lipid content and reduced incidence of plaque rupture in the CL. This study suggests that specific morphological features of the CL correlate with the flow grade following thrombolytic therapy in patients with STEMI.
Abstract 5418: Structural Alterations in Subcutaneous Small Resistance Arteries May Predict Changes of the Renal Function in Hypertensive Patients
Authors: Gianluca E Boari, Damiano Rizzoni, Enzo Porteri, Carolina De Ciuceis, Monica Mazza, Alida Brignani, Claudia Agabiti Rosei, Luigi Caimi, Enrico Agabiti Rosei
Journal: Circulation (2009)

We have previously demonstrated that structural alteration of subcutaneous small resistance arteries of hypertensive patients, as indicated by an increased media to lumen (M/L) ratio, has a strong prognostic significance. Among the predictors of M/L indicators of renal function are those more closely correlated. Aim of the present study was to assess whether M/L ratio can predict subsequent changes in renal function in hypertensive patients. Sixty patients (33 males; 27 females; 15 normotensives and 45 hypertensives) underwent a biopsy of subcutaneous fat at a mean age of 56 years. Resistance-sized arteries were dissected and mounted on a wire myograph according to Mulvany-Halpern technique, and M/L was measured. Patients were re-evaluated after a mean time period of 8.5 years; serum creatinine, blood urinary nitrogen (BUN) and uric acid were measured, and glomerular filtration rate (GFR) was calculated according to MDRD formula. At baseline, we observed significant correlations between M/L and serum creatinine (r=0.32; p=0.013), GFR (r= −0.26; p=0.047), BUN (r=0.37; p=0.009), systolic (r=0.45, p&lt;0.001), diastolic (r=0.29, p=0.02), mean blood pressure (r=0.38, p=0.002) and pulse pressure (r=0.40, p=0.002). In addition, we observed significant correlations between M/L and creatinine at follow up (r=0.57; p&lt;0.001), % changes in serum creatinine (r=0.46; p&lt;0.001), GFR at follow up (r= −0.43; p&lt;0.001); % changes in GFR (as ml/min r= −0.33; p=0.008), as well as yearly changes (r= −0.34, p=0.007), BUN at follow up, (r=0.55; p&lt;0.001), as well as uric acid at follow up (r=0.35; p=0.026). A multivariate analysis in which all common cardiovascular risk factors were included, showed that M/L is the most potent predictor of changes in renal function. In conclusion, our data suggest that structural alterations of subcutaneous small resistance arteries (which may be present also in other vascular beds), may predict the time-course of changes of renal function during a follow-up period of about 9 years.
Abstract 5309: Perforin-Independent Granzyme B-Mediated Extracellular Matrix Protein Cleavage Contributes to Abdominal Aortic Aneurysm
Authors: Lisa S Ang, Wendy A Boivin, Sarah J Williams, Ciara M Chamberlain, Hongyan Zhao, Michael F Allard, Bruce M McManus, David J Granville
Journal: Circulation (2009)

Background: Granzyme B (GrB) is a pro-apoptotic serine protease present in atherosclerotic human vessels, where its expression corresponds to increased disease severity and plaque instability. In addition to its perforin-dependent cytotoxic role, GrB accumulates extracellularly and contributes to the degradation of extracellular matrix (ECM) proteins. Hypothesis: GrB contributes to abdominal aortic aneurysm (AAA) through the cleavage of medial and/or adventitial ECM proteins. Methods : Human AAA and thoracic aortic aneurysm (TAA) samples were assessed for the presence of granzymes, immune cell markers, and ECM. Apolipoprotein E (apoE)−/− × GrB−/− double knockout (GDKO) and apoE−/− × perforin−/− DKO (PDKO) mice were generated to assess the functional intracellular and extracellular roles of GrB, respectively, in AAA. To induce AAA, mice were implanted with osmotic mini pumps containing angiotensin II (AII, 1000 ng/kg/min) or saline for 28 days. To further assess extracellular GrB activity, a novel serpin inhibitor of GrB was injected 3h prior to pump implantation. Survival, degree of AAA, ECM composition and GrB localization were evaluated. In vitro protease assays were performed to identify novel extracellular GrB substrates that may contribute to AAA. Results: While GrB was not present in healthy human aorta, GrB was abundantly expressed in the vessel wall and thrombus of aneurysmal tissue. AII-treated GDKO mice but not PDKO mice had increased 28-day survival (92.86%; n=14 vs. 56.25%, n=16) when compared to apoE-KO mice (53.33%; n=15). While AAA rupture was observed frequently in apoE-KO (46.7%; n=15) and PDKO (43.3%; n=16) mice, rupture was rarely observed in GDKO (7.1%; n=14) mice. Reduced degradation of medial fibrillin-1 and adventitial decorin and collagen was observed in the blood vessels of GDKO and serpin-treated mice versus apoE-KO mice. GrB localized to macrophages, mast cells and areas of medial disruption and adventitial weakening. Protease assays demonstrated GrB-cleavage of fibrillin-1 and decorin along with other ECM components. Conclusions: GrB contributes to the loss of vessel wall integrity and AAA through the cleavage of medial and adventitial ECM. Inhibition of GrB attenuates medial disruption and aortic rupture in mice.
Abstract 5281: Novel Role of p66shc in ROS-dependent VEGF Signaling and Cell-Cell Adhesions in Endothelial Cells
Authors: Jin Oshikawa, Ronald McKinney, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2009)

p66shc is an adaptor protein and functions as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. We demonstrated that VEGF stimulation rapidly increases ROS via activation of NADPH oxidase, which are involved in VEGF receptor 2 (VEGFR2) autophosphorylation as well as endothelial cell (EC) proliferation and migration. However, the role of p66shc in VEGF signaling has not been investigated. Here we show that VEGF stimulation increases serine phosphorylation of p66shc at Ser36 in ECs (3.1-fold at 5mins, 5.4-fold at 15mins). Adenovirus-mediated transfer of mutant p66shc (S36A) or knockdown of p66shc with siRNA decreases both basal- and VEGF-stimulated ROS levels, which results in inhibiting VEGF-induced VEGFR2 autophosphorylation (43.6% and 64.9%, respectively) as well as phosphorylation of p38MAPK (20.2% and 58.5%) and Akt (57.7% and 76.8%). Functionally, p66shc siRNA or overexpression of p66shc (S36A) inhibits VEGF-induced EC migration (58.6% and 50.9%) and proliferation (86.2% and 100%). Of note, immunofluorescence analysis reveals that p66shc is colocalized with and binds to VE-cadherin/beta-catenin complex at cell-cell contacts in confluent ECs, which is required for stabilizing cell-cell adhesions. Depletion of p66shc with siRNA disrupts VE-cadherin-beta-catenin complex, thereby reducing VE-cadherin localization at adherens junction and increasing endothelial permeability (40.8% increase), as measured by transendothelial electric resistance. Moreover, p66shc siRNA markedly reduces basal- and VEGF-stimulated stress fiber formation, which may contribute to a mislocalization of VE-cadherin. In summary, p66shc functions as a key regulator for ROS-dependent VEGF signaling linked to angiogenesis and actin reorganization as well as stabilizing cell-cell junctions. Thus, p66shc is a potential therapeutic target for angiogenesis-dependent cardiovascular diseases. 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).
Abstract 5414: Serum Uric Acid Levels versus the Abdominal Obesity in Relation to Incident Hypertension in a Prospective Study in a Chinese Community
Authors: Weili Zhang, Kai Sun, Ying Yang, HongYe Zhang, Rutai Hui
Journal: Circulation (2009)

BACKGROUND: Most Caucasian-based epidemiological data have shown that hyperuricemia is associated with the risk of hypertension, but whether this association is independent of adiposity and other vascular risk factors remains unclear. Therefore, we evaluated the associations of serum uric acid versus abdominal obesity with incident hypertension in a large Chinese Han population. METHODS: We conducted a community-based prospective cohort study comprising 7220 participants (mean age 37 years; 74% men) in the Qingdao Health and Nutrition Examination Survey in China, who were free from hypertension at study entry in 1999–2000. During 4-year follow-up, 1370 men (19.0%) and 208 women (11.0%) had developed hypertension. RESULTS: After adjustment for age, body mass index, waist circumference, and other covariates, the relative risks (RR) of developing hypertension according to uric acid quartiles were 0.97, 1.23, and 1.39 [95% confidence interval (CI), 1.16–1.68; P trend=0.008] for men and 1.49, 1.58, 1.85 (95%CI, 1.06–3.24; P trend=0.007) for women. The associations of hypertension with serum uric acid increased with the component number of metabolic syndrome (none, one, two, or more), which is defined by the criteria of the modified Adult Treatment Panel III and an Asian-specific waist circumference cut-off point (≥90 cm in men, ≥80 in women). Given that abdominal obesity is an important underlying risk factor for metabolic syndrome, in joint analyses of waist circumference and serum uric acid, participants with abdominal obesity had a consistently higher risk than those without. Compared with those in the lowest uric acid quartile and without abdominal obesity, participants who were in the highest quartile and also had abdominal obesity had a 3.0-fold and 3.4-fold greater risk of incident hypertension in men (95%CI, 1.56–2.97) and in women (95%CI, 2.10–3.81), respectively. To minimize the bias from reverse causality due to subclinical hypertension, analyses after excluding the first 2 years of follow-up showed similar results. CONCLUSIONS: These data suggest a positive association between serum uric acid and incident hypertension during short-term follow-up in a Chinese population. The association was partly mediated through abdominal obesity. 1
Abstract 5298: Staphylococcal Superantigen-like 5 Induces Platelet Activation and Thrombosis via Binding to GPIb <i>α</i> and GPVI
Authors: Houyuan Hu, Elie Khalil, Yung Chih Chen, Andreas Straub, Min Li, Fu Jia, Nicole Bassler, Dexing Huang, Ingo Ahrens, Elizabeth Gardiner, Karlheinz Peter
Journal: Circulation (2009)

Staphylococcus aureus (S. aureus) is a common and dangerous bacterial pathogen capable of causing life-threatening thromboembolic disease such as disseminated intravascular coagulation (DIC). S. aureus is known to secrete potent toxins that include Staphylococcal superantigen-like protein 5 (SSL5), which was recently shown to bind P-selectin glycoprotein ligand-1 (PSGL-1). As PSGL-1 is structurally and functionally related to the glycoprotein (GP) Ib α platelet receptor, this study assessed the ability of SSL5 to interact with GPIb α as well as other platelet glycoprotein receptors. Using flow cytometry, immunoprecipitation, surface plasmon resonance, platelet adhesion and aggregometry assays, recombinantly produced SSL5 was found to directly bind to platelet GPIb α via the sLacNac residues that terminate its glycan chains. SSL5 was also found to bind to the platelet collagen receptor GPVI. This binding of SSL5 to platelets causes platelet activation and aggregation as demonstrated in in vitro assays. SSL5 was subsequently tested for its prothrombotic effects in C57BL/6 mice. Pulmonary thrombi developed in 8 of 11 intraveneously SSL5-injected mice but were absent from 5 mice injected with a functionally-inactive SSL5 protein carrying a T175P point mutation. Further expriments using flow cytometry showed that SSL5-induced platelet activation was significantly inhibited by an anti-SSL5 monoclonal antibody designated 5E3 (10 μ g/ml, P &lt; 0.001), as well as sLe x (IC50 &lt; 5 μ M, P &lt; 0.001) and sLacNac glycans (IC50 &lt; 50 μ M, P &lt; 0.001). Moreover, the injection of 5E3 in SSL5-treated mice (n = 8) compared with mice only injected with SSL5 (n = 8), was found to inhibit SSL5-induced thrombus formation (P &lt; 0.05). Taken together, our data show that SSL5 binds to GPIb α and GPVI and as a consequence of this activates platelets and induces thrombosis. Thus, we describe a novel pathogenic mechanism potentially active in S. aureus infections. Furthermore, blockade of SSL5-induced platelet activation and thrombosis by either 5E3 or inhibitory glycans defines a novel treatment strategy and identifies suitable drug candidates for prevention and treatment of thrombotic diseases associated with S. aureus infections.
Abstract 5315: Receptors for Advanced Glycation Endproducts Cause Decreased Collateral Vessel Formation in the Face of Uncontrolled Diabetes
Authors: Divya Gupta, Daiana Weiss, Natalia Landazuri, Catherine Norton, Robert E Guldberg, W R Taylor
Journal: Circulation (2009)

Introduction: Diabetes Mellitus (DM) is associated with the development of poor collateral vasculature. The precise cellular and molecular processes are not well understood, but monocytes (MO) play a critical role. Chronic DM leads to the formation of advanced glycation endproducts (AGEs) which alter molecular functions through the Receptor for Advanced Glycation Endproducts (RAGE). The major goal of this study was to explore the contribution of RAGE to impaired collateral growth in the setting of DM, specifically when absent from MO. Hypothesis: Decreased RAGE on MO leads to improved collateral vasculature in the setting of hyperglycemia. Methods : Four groups of mice on a C57/Bl6 background were created: Wild type (WT), WT + DM, RAGE Knockout (RAGE KO), RAGE KO + DM. Streptozocin was given intraperitoneally to induce DM. After 4 weeks of DM, the left femoral artery was ligated for a hind limb ischemia model. Laser Doppler Perfusion Imaging (LDPI) was used for qualitative evaluation of collateral vessel development. Alpha-actin smooth muscle staining was used for quantitative anatomic evaluation of neovascularization. Spontaneous running duration was employed as a functional endpoint. Adoptive transfer was used to assess MO involvement. WT + DM mice were injected with RAGE KO MO and RAGE KO + DM mice were injected with WT MO on post-op days 0,2,5,7. LDPI was performed on post-op days 1 and 8 Results : WT + DM mice had the lowest level of blood flow recovery of all three groups, with a significant difference when compared to RAGE KO + DM (34% +/− 6.3%, 80.8 %+/− 12%; p&lt; 0.001). These significant differences between WT + DM and RAGE KO + DM mice were also present when assessing data obtained from the running wheels (463m +/− 34m, 40, 938m +/− 342m; p&lt;0.001) and histology when assessing the number of new vessels(v) (−9.6v +/− 38.2v, 409.1v +/− 86.9v; p&lt; 0.05). Perfusion ratios were increased in WT + DM mice treated with RAGE KO MO by LDPI on post-op day 8 when compared to perfusion ratios seen in WT + DM mice without RAGE KO MO injection when normalized to the perfusion ratios obtained on post-op day1 (2.3% +/− 0.6% v. 1.04% +/− 0.09%; p&lt; 0.05). Conclusions : RAGE on MO appears to play a significant role in the hindrance of collateral vessel development in the face of hyperglycemia.