tbuckley/cabot-search huggingface dataset:
Abstract 5270: Vascular Function and Vascular Inflammation in Polycystic Kidney Disease
Authors: Kevin S Heffernan, D Rudym, Jeffrey T Kuvin, Richard H Karas, D Miskulin, R Perrone, M Sarnak, V Menon
Journal: Circulation (2009)

Background: Polycystins, which have been localized to vascular smooth muscle cells, may lead to vascular dysfunction and contribute to cardiovascular disease in autosomal dominant polycystic kidney disease (ADPKD). We examined vascular function and vascular inflammation in ADPKD. Methods: This is an ancillary study to the Halt Progression in PKD Study, which is examining the effect of renin-angiotensin-aldosterone blockade on progression of ADPKD. We used peripheral arterial tonometry to assess augmentation index (AIx), a measure of arterial stiffness and wave reflection, in 52 ADPKD patients with hypertension and glomerular filtration rate (GFR) 25– 60 ml/min/1.73 m 2 , 50 ADPKD patients with hypertension and GFR &gt;60 ml/min/1.73 m 2 , and 51 healthy controls. We measured serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (VCAM-1), p-selectin, e-selectin, soluble Fas, and Fas ligand (FasL) as markers of vascular inflammation. Results: AIx, sICAM, p-selectin, and Fas were higher, and FasL was lower in subjects with ADPKD (p&lt;0.05, Table ). Adjusting for age, race, height, heart rate, and mean arterial pressure had no effect on group differences in AIx (healthy control = 8%, ADPKD GFR &gt;60 = 21%, ADPKD GFR 25– 60 = 20%). Group means were significantly different even after adjustment for vascular inflammatory markers (healthy control = 3%, ADPKD GFR &gt;60 = 24%, ADPKD GFR 25– 60 = 24%). There were no differences in AIx, sICAM, p-selectin, e-selectin, or FasL between the two ADPKD groups (Table 1 , p&gt;0.05). Conclusion: Vascular dysfunction and vascular inflammation are evident even in early stages of ADPKD with preserved GFR. Further research is needed to examine the relative contributions of genetic aberrations, hypertension, and reduced kidney function to the pathophysiology of vascular dysfunction in ADPKD. Table. Subject information.
Abstract 5430: Statins Exert Pleiotropic Effects by Enhancement of BMPER Expression via the Rho/Rock Pathway in Endothelial Cells
Authors: Thomas Helbing, Rene Rothweiler, Jennifer Heinke, Lena Goetz, Philipp Diehl, Cam Patterson, Christoph Bode, Martin Moser
Journal: Circulation (2009)

Background Statins exert pleiotropic effects on endothelial cells besides cholesterol lowering. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMPER, a novel member of the BMP pathway. Methods and Results Mevastatin or simvastatin enhanced BMPER expression in endothelial cells in a time and concentration dependent manner as determined by immunocytochemistry, RT-PCR, and western blotting. Actinomycin D chase analysis and BMPER promoter studies with reporter assays revealed that this is predominantly a post-transcriptional effect resulting in a prolonged BMPER RNA half-life. Rescue experiments using downstream metabolites of the HMG-CoA pathway (mevalonate, GPP, GGPP) suggested that the RhoA/Rock/actin pathway would be involved in BMPER regulation. Indeed we confirmed that the RhoA/Rock/actin pathway is essential for BMPER regulation using the specific pathway activator CNFY. CNFY prevented the upregulation of BMPER by mevastatin whereas pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, cytochalasin D) enhanced BMPER expression. As reflected by ICAM-1 regulation BMPER has anti-inflammatory features. Increasing concentrations of BMPER reduced ICAM-1 expression while silencing of BMPER increased ICAM-1 in endothelial cells. Remarkably, mevastatin reduced the expression of proinflammatory BMP4, a direct interaction partner of BMPER. Conclusion Mevastatin modulates the BMP pathway by enhancing BMPER expression via the RhoA/Rock/actin pathway as well as by inhibiting BMP4 expression. BMP4 down- and BMPER upregulation contribute to the anti-inflammatory pleiotropic effects of statins and represent a novel pleiotropic mechanism.
Abstract 5429: Bone Marrow-derived Cells Contribute to Vascular Inflammation but Do Not Differentiate Into Smooth Muscle Cell Lineages
Authors: Hiroshi Iwata, Ichiro Manabe, Katsuhito Fujiu, Norifumi Takeda, Kosei Eguchi, Masataka Sata, Ryozo Nagai
Journal: Circulation (2009)

It has been proposed that bone marrow-derived cells infiltrate the neointima, where they differentiate into smooth muscle cells (SMCs). This is based on the observation that those cells express SM α -actin; however, technical limitations have hindered clear identification of the lineages of bone marrow-derived “SMC-like” cells. Using a specific antibody against the definitive SMC-lineage marker SM myosin heavy chain (SM-MHC) and mouse lines in which reporter genes were driven by regulatory programs for either SM-MHC or SM α -actin, we demonstrated that while some bone marrow-derived cells express SM α -actin in the wire injury-induced neointima, those cells did not express SM-MHC, even 30 weeks after injury. Likewise, no SM-MHC+ bone marrow-derived cells were found in vascular lesions in apolipoprotein E−/− mice or in a heart transplantation vasculopathy model. Instead, the majority of bone marrow-derived SM α -actin+ cells expressed monocyte/macrophage markers, and expression of inflammation-related genes was significantly higher in neointimal subregions rich in bone marrow-derived SM α -actin+ cells than in other regions. In addition, flow cytometric analysis showed that bone marrow-derived SM α -actin+ cells were also CD115+ CD11b+ F4/80+ Ly6c+ CD11c−, which is the surface phenotype of inflammatory monocytes. It thus appears that bone marrow-derived cells are of monocyte/macrophage lineage and acquire a phenotype in which SMC early differentiation markers are expressed. Although these cells are involved in remodeling at active lesions in the severely injured vessel wall, it is very unlikely they acquire the definitive SMC lineage.
Abstract 5075: Beneficial Effects of Combination of ACE Inhibitor and Rho-kinase Inhibitor on Tubulointerstitial Fibrosis Induced by Unilateral Ureteral Obstruction
Authors: Toshio Nishikimi, Yosuke Takeda, Kimihiko Ishimura, Kazuyoshi Tadokoro, Chikako Iemura-Inaba, Kazumi Akimoto, Toshihiko Ishimitsu, Hiroaki Matsuoka
Journal: Circulation (2009)

Objects: We recently reported that long-term Rho-kinase inhibition attenuates glomerulosclerosis in severe hypertension, salt-induced hypertension, and malignant hypertension rat model. In addition, ACE inhibitor is well known to prevent renal fibrosis. This study was design to compare the effects of ACE inhibitor (imidapril), Rho-kinase inhibitor (fasudil), and their combination on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Methods: Imidapril (50mg/L), fasudil (1g/L), or their combination was given in drinking water to mouse (C57BL/6, each group: n =8), and their effects were compared on renal interstitial fibrosis induced by UUO. We measured histological findings, immunohistological findings, oxidative stress, and various mRNA expressions in the kidney by UUO. Results: Eleven days after UUO, wild type kidney was characterized increased fibrotic area (Masson’s trichrome stain positive area), dihydroethidium (DHE) positive area, α -SMA positive area, F4/80 positive area, and increased various mRNA expressions. Fasudil and imidapril similarly improved fibrotic area (−23%, −15%), DHE positive area (−13%, −11%), α -SMA positive area (−22%, −15%), F4/80 positive area (−42%, −34%), and various mRNA expressions (TGF- β : −20%, −18%; CollagenI: −37%, −19%; CollagenIII: −36%, −26%; MCP-1: −22%, −34%, TNF- α : −7%, −13%), most of which were significant (P&lt; 0.05). Combination of imidapril and fasudil further improved fibrotic area (−52%), DHE positive area (−26%), α -SMA positive area (−33%), F4/80 positive area (−62%), and various mRNA expressions (TGF- β :−48%; CollagenI:−65%; CollagenIII:−59%; MCP-1:−54%, TNF- α : −33%) (all P &lt;0.05 vs monotherapy). Conclusion: Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor is more effective in the prevention of renal interstitial fibrosis due to inhibition of TGF- β /collagen, migration of monocyte/macrophage, differentiation of fibroblast, inflammation, and oxidative stress pathway. Combination of an ACE inhibitor and a Rho-kinase inhibitor may be a possible new therapeutic strategy for chronic kidney disease.
Abstract 5205: Aortic Arch Calcification Detectable on Chest X-ray is a Strong Independent Predictor of Cardiovascular Events Beyond Traditional Risk Factors
Authors: Katsuya Iijima, Bo-Kyung Son, Hidetaka Ota, Sumito Ogawa, Masato Eto, Masayoshi Hashimoto, Masahiro Akishita, Yasuyoshi Ouchi
Journal: Circulation (2009)

Background: Aortic stiffness resulting from calcification makes management of hemodynamic status more difficult. Some reports have previously shown that simple assessment of aortic calcification in aortic arch and abdominal aorta using plain radiography can predict cardiovascular (CV) events. However, these studies simply assessed whether aortic calcification detectable on X-ray was present or absent, without considering the grade of calcification. In this study, we evaluated the validity and usefulness of grading aortic arch calcification (AAC) to predict new CV events, and compared it to traditional atherosclerotic risk factors. Methods and Results: This study enrolled 239 asymptomatic outpatients (mean age 61±14 years) without previous CV events. We divided the extent of AAC into four grades (from 0 to 3) by reviewing a postero-anterior plain chest X-ray. AAC grade was 0, 1, 2, and 3 in 46%, 22%, 29%, and 4% of the subjects, respectively. AAC grade was positively related to age, prevalence of diabetes and chronic kidney disease (CKD), and showed a significant association with clustering of traditional risk factors. In addition, impairment of endothelial function, as determined by flow-mediated dilation (FMD), was also associated with increasing AAC grade. Thirty two new CV events in total occurred during a mean follow-up period of 40±19 months. With multivariate adjustment, Kaplan-Meier analysis showed that the new incidence of CV events was significantly higher in patients with high AAC grade (grades 2 and 3) than in those with grade 0 or 1 (p&lt;0.01, log-rank test). Multivariate Cox-proportional hazards analysis showed that the predictive value of AAC grade for CV events was significantly stronger (hazard ratio, 1.8; 95% confidence interval, 1.2–2.8; p &lt;0.01) than that of FMD, HbA1c, and estimated GFR. In addition, predictive usefulness was found even in patients without CKD. Conclusion: AAC detectable on chest X-ray is a strong independent predictor of CV events. Beyond traditional risk factors including endothelial dysfunction, risk stratification by assessment of AAC may provide important information for primary preventive management of atherosclerotic disease.
Abstract 4873: Superiority of Polymer-free Cerivastatin-eluting Stent Over Polymer-based Paclitaxel-eluting Stent for Neointimal Inhibition and Vasomotor Function Preservation in Rabbit Iliac Arteries
Authors: Lakshmana Pendyala, Jinsheng Li, Xinhua Yin, Traci Goodchild, Sara Geva, Jack Chen, Nicolas Chronos, Dongming Hou
Journal: Circulation (2009)

Objectives: The present study was designed to evaluate and compare endothelial function and vascular biological responses following implantation of a novel, non-polymeric cerivastatin-eluting stent (CES) versus polymer-based paclitaxel-eluting stent (PES) in a rabbit iliac artery model. Methods : In vitro, human aortic and coronary smooth muscle cells (hASMC &amp; hCSMC), as well as aortic and coronary endothelial cells (hAEC &amp; hCEC), were cultured; and IC50 curves were determined for cerivastatin (CER). In vivo PES (n=6), CES (n=12), and polymer-free sol-gel only (sol-gel, n=12) stents were implanted in 15 rabbits. Vasomotor function was investigated at 28 days by infusion of acetylcholine (Ach) and nitroglycerin (NTG). Animals were terminated for histopathological analyses. Results: CER was cytotoxic to hASMC and hCSMC (IC50s of 10 −6 M and 10 −5 M, respectively), although such cytotoxic effects were not observed for hAEC and hCEC at maximal study dose. PES-associated vasodilation response to endothelial-dependent Ach was significantly suppressed at both proximal and distal adjacent arterial segments, as compared to CES and sol-gel. Furthermore, microscopically, the percent area stenosis was higher for PES (25±3%) compared to both CES and sol-gel (15±6% and 16±7%, p &lt; 0.05, respectively). Medial area was lower for PES (0.3±0.04 mm 2 ) than CES and sol-gel (0.5±0.03 and 0.4±0.04 mm 2 , p &lt;0.001, respectively). Additionally, re-endothelialization scores were comparable among groups ( P =NS); but profound fibrin deposition was clearly evidenced in PES ( p &lt; 0.05 vs. others). Conclusions: CER elicits a differential effect on hSMC compared to hEC in vitro. In contrast to PES, a novel bioabsorbable sol-gel coated CES demonstrated superior neointimal inhibition and less vessel toxicity, as well as preservation of vasomotor function in the rabbit iliac model.
Abstract 5163: Genetic Deletion of OX40 Ligand Suppresses the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice
Authors: Makoto Nakano, Yoshihiro Fukumoto, Kimio Satoh, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa
Journal: Circulation (2009)

Background: Atherosclerotic lesions are characterized by infiltration of inflammatory cells, for which immunological mechanism may be involved. Furthermore, it has been previously demonstrated that immune system is involved in post-ischemic angiogenesis and that atherosclerosis is associated with enhanced vasa vasorum formation. Both soluble and contact-dependent mediators from T-cells play a crucial role in the development of atherosclerosis. OX40, a membrane-bound molecule of the tumor-necrosis-factor-receptor superfamily, is expressed in activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we examined whether OX40/OX40L system is involved in the pathogenesis of atherosclerosis, especially in terms of vasa vasorum formation. Method and Results: We first demonstrated that endothelial cells of the deep intima in human coronary atheroma were immunopositive for OX40L (n=5). We then examined whether or not the OX40/OX40L system influences the development of atherosclerosis in apolipoprotein E-deficient (ApoE −/− ) mice. ApoE −/− mice and ApoE −/− /OX40L-double-deficient (ApoE −/− /OX40L −/− ) mice were fed on a high-fat diet starting at 4 weeks of age. After 8 weeks, aortic en face and aortic root analysis with oil-red O staining demonstrated that the extent of aortic atheroma was significantly less in ApoE −/− /OX40L −/− mice as compared with ApoE −/− mice (9.6±2.2% vs. 13.6±3.5%, P&lt;0.01, 8.1±4.3% vs. 12.7±7.4%, P&lt;0.05, n=16, respectively). To elucidate the role of OX40L in vasa vasorum formation for atherogenesis, we examined adventitial vascularity by immunostaining and confirmed that the number of blood vessels in adventitia was significantly less in ApoE −/− /OX40L −/− mice as compared with ApoE −/− mice (16.0±3.2 vs. 33.5±16.1 vessels/HPF, P&lt;0.01, n=8). Furthermore, capillary formation in implanted matrigel was significantly less in OX40L −/− mice as compared with WT mice. Conclusions: These results indicate that the OX40/OX40L system plays an important role in neovascularization of atheroma, which may promote the atherosclerotic process, suggesting that the OX40/OX40L system could be a new therapeutic target for the treatment of atherosclerosis.
Abstract 5445: Tissue Kallikrein Deficiency Impairs Circulating Proangiogenic Cells Invasive Capacity
Authors: Gaia Spinetti, Orazio Fortunato, Daniela Cordella, Francois Alhenc-Gelas, Christine Ritcher, Marie-Pascale Vincent, Giancarlo Tonolo, Sara Cherchi, Costanza Emanueli, Paolo R Madeddu
Journal: Circulation (2009)

Background: Circulating proangiogenic cells (PACs) express the serine protease tissue kallikrein (K1), which favours invasion through metalloproteinases activation. Aim: To determine whether inherited or disease-induced K1 deficiency alters PACs migration and proangiogenic capacity, and whether K1-deficient PACs transduction with wild type or polymorphic variant (R53H) K1 can rescue functional defects. Methods &amp; Results: Wild type (WT, n=8) or K1-knockout mice (K1KO, n=7) lineage negative (Lin-) bone marrow mononuclear cells (BMMNC) were used in migration assays or differentiated into PACs. K1KO Lin-BMMNC showed defective migration to SDF-1 α compared to WT (fold increase vs vehicle 2.2, p=N.S and 5.8, p&lt;0.05 vs vehicle and K1KO, respectively, n=3). Similarly impaired was K1KO PACs migration (n=3, p&lt;0.05 vs WT). Further, K1KO PACs were unable to promote endothelial cell (EC) networking in vitro (p&lt;0.05). Adenovirus-mediated K1 transduction rescued both defects in K1KO PACs (n=3, p&lt;0.05 vs Ad.Null). Next, we studied type 2 diabetic patients and age-matched healthy controls circulating PACs (n&lt;6 per group). Diabetic PACs showed reduced migration and proangiogenic potential (−1.8 and 2.0 fold vs controls, p&lt;0.05) and lower K1 protein (−56.6 %, p&lt;0.05), but normal K1 mRNA abundance, pointing at a post-transcriptional defect. K1 overexpression increased healthy PACs migration and EC networking (p&lt;0.01 vs Ad.Null), but could not revert diabetic PACs liabilities (p±N.S. vs Ad.Null). We then verified if K1 increases PACs invasive capacity. K1-PACs invaded matrix more efficiently (2.5-fold increase, p&lt;0.01 vs Null-PACs). In contrast, the polymorphic variant R53H, which encodes for an enzymatic defective K1 form, did not improve invasion. Moreover, K1-PACs failed to invade the matrix when regular collagen was substituted with glycated one. Conclusions: Inherited or diabetes-induced K1 deficit hampers PACs invasive and proangiogenic capacities, with K1 gene therapy being able to restore those functions except in diabetes. Diabetes could interfere with K1 enzymatic activity and make extracellular matrix impenetrable to PACs. Alternatively, additional migratory machinery deficit may overwhelm benefits of K1 overexpression.
Abstract 4182: Endogenous Estrogen and Risk of Stroke in Elderly Men: The Honolulu Heart Program
Authors: Beatriz L Rodriguez, Robert Abbott, Peter W Wilson, Lenore J Launer, G W Ross, Kamal H Masaki, D Strozyk, Katsuhiko Yano, Jordan S Popper, Helen Petrovitch, J. D Curb
Journal: Circulation (2006)

Background : Little is known about the relationship between endogenous estrogen and the risk of stroke, particularly in elderly men. The purpose of this report is to determine if levels of total and bioavailable endogenous estrogen and testosterone can predict stroke in a population-based sample of elderly men. Methods : Endogenous estrogen and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu Heart Program from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. Results : During the course of follow-up, 124 men developed a stroke (9.1/1000 person-years). After age-adjustment, men in the top quintile of bioavailable estrogen (&gt;82.8 pmol/L [22.6 pg/mL]) experienced a 2-fold excess risk of stroke versus men whose estrogen levels were lower (15.5 vs 7.5/1000 person-years, p&lt;0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for total estrogen and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, the relationship between estrogen and stroke between the top versus lower quintiles persisted (relative hazards = 2.2; 95% confidence interval = 1.4 − 3.3, p&lt;0.001). Testosterone was not related to the risk of stroke. Conclusions : Findings suggest that high levels of endogenous estrogen are associated with an elevated risk of stroke in elderly men.
Abstract 5121: Sustained Impairment of Endothelial Vasomotor Function Predicts Development of Renal Dysfunction in Patients With Chronic Ischemic Heart Disease
Authors: Isao Takishima, Yoshinobu Kitta, Mitsumasa Hirano, Takamitsu Nakamura, Yuri Ino, Aritaka Makino, Keita Sano, Yukio Saito, Yasushi Kodama, Jun-ei Obata, Ken-ichi Kawabata, Kiyotaka Kugiyama
Journal: Circulation (2009)

Endothelial dysfunction in systemic arteries is associated with renal dysfunction. It is unclear whether reversibility of endothelial dysfunction in systemic arteries in response to risk factors reduction has prognostic value for future renal dysfunction. This study examined whether changes in endothelial vasomotor function in the brachial artery after optimized therapy for coronary artery disease (CAD) predict the development of renal dysfunction. Methods: This study included 214 patients with newly diagnosed chronic CAD who had an impaired flow-mediated dilation (FMD) of the brachial artery and chronic kidney disease (CKD) stage 1 or 2 at enrollment. After enrollment, all patients had individualized, optimized therapies including medications and life style changes based on AHA guidelines to reduce risk factors for CAD. Measurement of FMD was repeated at enrollment (1 st test) and 6 months after therapies were initiated (2 nd test). Thereafter, all patients continued their same medications and were prospectively followed for ≤ 36 months or until the progression to CKD stage 3. Impairment of FMD was defined as &lt; 5.5% (mean minus 1 SD of FMD in 100 age- and sex-matched normal subjects). Results: FMD was persistently impaired (&lt; 5.5%) in 114 (53.2%) patients at the 2 nd test, whereas it was improved (FMD ≥ 5.5%) in the remaining 100 (46.7%) patients. During the follow-up period, the progression to CKD stage 3 occurred in 46 (40%) patients with persistently impaired FMD and in 21 (21%) patients with improved FMD (p &lt; 0.01). Multivariate Cox proportional hazards analysis showed that persistent impairment of FMD was a significant predictor of the progression to CKD stage 3 (HR 2.04, 95% CI 1.1 - 3.9, p &lt; 0.01) that was independent of 1 st FMD, hypertension, diabetes, and age. Using a c -statistic, the predictive value of persistently impaired FMD was incremental over that of 1 st FMD, hypertension, diabetes and age (area under the ROC curve; 0.80 and 0.71, respectively, p = 0.01). Conclusions: Persistent impairment of endothelial vasomotor function despite optimized therapy to reduce CAD risk factors is an independent predictor of the development of renal dysfunction. The periodic measurement of FMD is useful for risk stratification for future renal dysfunction.