tbuckley/cabot-search huggingface dataset:
Abstract 5156: Plasma Des-acyl Ghrelin, but Not Plasma HMW Adiponectin, is a Useful Cardiometabolic Marker for Predicting Atherosclerosis in Elderly Hypertensive Patients
Authors: Yuichiro Yano, Koji Toshinai, Takashi Inokuchi, Kazuyuki Shimada, Kazuomi Kario, Masamitsu Nakazato
Journal: Circulation (2009)

Objective: The coming obesity epidemic in elderly persons necessitates the establishment of new and easy-to-use cardiometabolic markers to identify individuals most likely to develop atherosclerosis among elderly hypertensive patients. Methods: We measured plasma high-molecular-weight (HMW) adiponectin and des-acyl ghrelin levels, and carotid artery intima-media thickness (cIMT) in 263 elderly hypertensive patients (mean 72.6 years; 37% men). Other cardiometabolic markers, including lipid and glucose metabolites, inflammation (high-sensitivity C-reactive protein: hs-CRP), and hemostasis (plasminogen activator inhibitor-1: PAI-1), were also measured. Results and conclusion: Both HMW adiponectin and des-acyl ghrelin levels were inversely correlated with obesity (both P &lt;0.01). The HMW adiponectin level was favorably associated with glucose and lipid metabolites, PAI-1(all P &lt;0.05), and hs-CRP ( P &lt;0.07) after adjustment for age, sex, and BMI; however, it had no correlations with cIMT. In contrast, although there were no correlations between des-acyl ghrelin and any cardiometabolic markers, except for a positive association with the nitrite/nitrate (NOx) level ( P =0.002), des-acyl ghrelin had a significant inverse correlation with cIMT ( P =0.003). A multivariable regression analysis showed that des-acyl ghrelin, but not HMW adiponectin, was significantly associated with cIMT after adjusting for age, obesity, sex, smoking, 24-hour BP, and other cardiometabolic factors ( β =−0.178, P=0.001). Moreover, receiver-operator curves to predict a high level of cIMT (above median) demonstrated that des-acyl ghrelin was the best predictor (area under the curve=0.622, P =0.001). The increased risk of cIMT among those with abdominal obesity compared with non-obesity (0.833±0.185mm vs. 0.782±0.163mm, P =0.019) was explained by the elevated 24-hour BP and reduced des-acyl ghrelin level, but not by other cardiometabolic parameters. These associations were unchanged after adding NOx to the model. In conclusion, the des-acyl ghrelin level is a useful cardiometabolic marker for predicting atherosclerosis in elderly hypertensive patients, and the pathologic pathway linking these factors is independent of its NO bioactivity.
Abstract 5116: Stable Arteriogenesis of Ischemic Hind Limbs by a Conditionally Silenced AAV9 Gene Therapy Vector Expressing Human VEGF
Authors: Jeffrey Boden, Keith A Webster
Journal: Circulation (2009)

INTRODUCTION: Therapeutic angiogenesis to treat coronary and peripheral artery disease with genes or cells has not been successful. RATIONALE: Previous protocols focused on angiogenesis with two major flaws Inadequate delivery vehicles Use of unregulated genes with no directional cues for new vessel growth. HYPOTHESIS: VEGF gene delivery in a semipermanent muscle-tropic AAV9 vector with tight hypoxia-regulation supports directional angiogenesis, arteriogenesis and stable reperfusion. METHODS: The human (h)VEGF gene driven by a PGK promoter containing tandem arrays of HIF-1 α and NSF (silencer) binding sites was cloned into AAV9. Gene expression and regulation were quantified in myocytes and ischemic hind limbs of normal and atherosclerosis-prone mice. Arteriogenesis was evaluated in ischemic hind limbs with intramuscular delivery. RESULTS: Systemic delivery of AAV9-HR-VEGF to mice showed high tropism for muscle with a 3-fold greater preference for cardiac over skeletal muscle. VEGF expression from AAV9-HR-hVEGF was negligible in aerobic myocytes or normally perfused hind limb and displayed 50 –100-fold induction by hypoxia. Concurrent atherosclerosis muted transgene expression. Delivery of AAV9-HR-hVEGF to ischemic hind limbs supported a progressive increase of limb perfusion that reached 87% of the contra lateral limb after 12 weeks and was sustained at 40 weeks. Limps treated with PBS or adenoviral-hVEGF auto-amputated at 12 weeks. Immunohistology of hind limbs at 2, 4, 12, 16 and 30 weeks revealed significantly larger vessels containing smooth muscle actin in limbs treated with AAV9-HR-VEGF compared with an unregulated vector. DiI imaging combined with scanning confocal microscopy revealed a progressive longitudinal (hip to foot) growth of vessels with the appearance of arteries at 16-weeks. HVEGF expression peaked at 12 weeks and declined thereafter, confirming regulation by ischemia. CONCLUSION: Sustained, ischemia-regulated VEGF expression supports early angiogenesis that evolves into arteriogenesis with the generation of stable vessels, muscle perfusion and limb salvage. Down-regulation of the transgene coincident with therapy provides a safety switch that will allow the clinical translation of this strategy.
Abstract 4965: High Mobility Group Box 1 Protein Expression is Associated With Expansion and Rupture of Human Abdominal Aortic Aneurysm
Authors: Takashi Kohno, Toshihisa Anzai, Hidehiro Kaneko, Hideyuki Shimizu, Masayuki Shimoda, Taku Miyasho, Minoru Okamoto, Hiroshi Yokota, Shingo Yamada, Tsutomu Yoshikawa, Yasunori Okada, Akitoshi Ishizaka, Ryohei Yozu, Satoshi Ogawa
Journal: Circulation (2009)

Background: Abdominal aortic aneurysm (AAA) expansion is characterized by widespread transmural inflammation and extracellular matrix degradation. High mobility group box1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic and activated inflammatory cells, and functions as a proinflammatory mediator. The aim of this study was to elucidate the clinical significance of HMGB1 expression in patients with AAA. Methods and Results: Serum HMGB1 concentration was measured by enzyme-linked immunosorbent assay in 40 patients with infrarenal AAA (6 patients with ruptured and 34 patients with nonruptured AAA), who underwent surgical repair of AAA. Serum HMGB1 level on admission did not differ between the presence or absence of atherosclerotic risk factors, including smoking, hypertension, hyperlipidemia, age and sex, and cardiovascular medications. These variables were similar between patients with ruptured and nonruptured AAA. Serum HMGB1 level was significantly higher in patients with ruptured AAA compared with nonruptured AAA (4.9±3.4 vs 1.9±2.9 ng/ml, p&lt;0.05). Thirty-eight AAA tissues taken during surgical repair were examined for immunoblotting (4 ruptured and 34 nonruptured AAA). The HMGB1 level in aneurysmal tissue was positively correlated with AAA diameter (r=0.43, p&lt;0.05). In addition, HMGB1 expression was higher in patients with ruptured AAA than those with nonruptured AAA (p&lt;0.05). Gelatin zymography showed that matrix metalloproteinase (MMP)-2 and -9 levels were significantly elevated in the ruptured AAA compared with nonruptured AAA (all p&lt;0.05). Patients with MMP-2 level&gt;median value had a higher HMGB1 level in aneurysmal tissue than those without (p&lt;0.05). Immunohistochemistry demonstrated that HMGB1 was highly expressed in macrophages and neutrophils within the degenerating aortic media and periadvential fat tissues of AAA. HMGB1 was also expressed in smooth muscle cells and fibroblasts within the degenerating aortic media. Conclusions: Elevation of HMGB1 level in serum and aneurysmal tissue was observed in patients with expansion and rupture of AAA, in association with activation of MMPs. Serum HMGB1 could be a useful marker of the development of AAA rupture.
Abstract 5443: Osteopontin Stimulates Secretion of Angiogenic Proteins in Endothelial Progenitor Cells
Authors: Erin E Vaughan, Angela Duffy, Timothy O’Brien
Journal: Circulation (2009)

Patients with Type 1 Diabetes Mellitus (T1DM) often demonstrate an ineffective angiogenic response to ischemia. This may be due to a decrease in the number and function of their endothelial progenitor cells (EPC). EPC are promising cells for autologous cell transplantation in the treatment of T1DM hence it is imperative to understand the underlying cause of their dysfunction. Therefore, we identified proteins that are dysregulated in EPC from patients with T1DM. Osteopontin (OPN), a secreted protein involved in cell migration, cell survival, and tumour growth was found to be down regulated. Thus, we hypothesized that OPN down regulation in T1DM EPC contributes to a decreased angiogenic response. To elucidate the role of OPN in EPC, EPC were isolated from OPN knockout (KO) mice and wild type mice (WT) for a matrigel tubule assay to assess in vitro angiogenic potential. KO EPC induced significantly less tubule formation than WT EPC (p&lt;.05, n=3). Knockout EPC that were pre-incubated with recombinant OPN induced tubule formation at levels similar to WT and significantly higher than KO cells that were not incubated with OPN (p&lt;.05, n=3). Further, conditioned media (CM) from WT cells induced tubule formation to the same levels as the EPCs themselves suggesting that secreted proteins are responsible for the angiogenic effect. Interestingly, when KO EPC were pre-incubated with OPN, washed, and fed with new media the CM media induced tubule formation to WT levels(n=3), even though there was no OPN directly in the media. Hence, we further hypothesized that OPN is acting on EPC to induce the secretion of angiogenic cytokines. To test this, a chemi-array was performed on EPC from WT, KO and KO exposed to OPN. WT EPCs expressed FGF α at a much higher level than KO cells. Expression of FGF was restored to WT levels when KO cells were pre-incubated with OPN. Further, WT cells expressed Il-6 and TGF- α whereas KO cells did not express these proteins at detectable levels. Interestingly, when KO cells are exposed to OPN both IL-6 and TGF- α are expressed at WT levels. Taken together, this data suggests that OPN expression increases the angiogenic potential of EPCs via an autocrine mechanism whereby OPN is secreted by the EPC and subsequently induces the expression of a variety of angiogenic proteins.
Abstract 5427: Regulation of Arterial Branching Morphogenesis by Notch Ligand Delta-like 1
Authors: Florian P Limbourg, Jeanette Woiterski, Michael Augustynik, L C Napp, Anne Limbourg, Helmut Drexler
Journal: Circulation (2009)

Arterial development and homeostasis are regulated by genetic factors and hemodynamic forces but how hemodynamic forces shape arterial branching morphogenesis and whether there is cross-talk to genetic programms is largely unknown. Here we show that the Notch ligand Delta-like 1 (Dll1) is regulated by hemodynamic forces to regulate arterial branching morphogenesis and adult arterial phenotype in vivo. RESULTS: The onset of Dll1 expression was observed in fetal arteries at embryonic day E12.5, concurrent with the establishment of proper arterial circulation. Dll1 expression was restricted to endothelial cells (EC) of arteries and absent in veins or capillaries. Arterial branching morphogenesis in the developing retinal vasculature was significantly reduced in Dll1+/− mice, which lacked arterial branches forming the secondary vascular plexus. To test the influence of hemodynamic forces on Dll1 expression we exposed human aortic EC to cyclic stretch in vitro (10 and 15%), which upregulated Dll1 mRNA and protein levels and activated Notch target gene expression of Hes1 in a time-dependent manner. Dll1 regulation by hemodynamic forces had a strong impact on the branching phenotype of adult coronary arteries. Whole-mount ink perfusion and SMA-stained ventricular cross sections demonstrated significant rarefication of small, medium and large coronary arteries of Dll1+/− mice (p&lt;0.01), while the number of microvessels was significantly increased (p&lt;0.01). Quantification of the perfusion territory of the left descending coronary artery (LAD) by Evans blue perfusion revealed a significantly reduced perfusion territory in Dll1+/− mice (37±5% of wt, p&lt;0.01), consistent with a regulation of coronary branching and extension by Dll1. Notably, while body size was normal, heart weight and LV dimensions were reduced in Dll1+/− mice, but EF was increased to maintain a normal stroke volume and cardiac output. To test whether hemodynamic forces regulate Dll1 expression in vivo we occluded the LAD and performed Dll1 stainings in sections 24hrs after occlusion, which revealed downregulation of EC Dll1. CONCLUSION: Hemodynamic forces regulate Dll1 which regulates arterial branching morphogenesis during development and postnatal life.
Abstract 573: Abnormal Impulse Propagation and Susceptibility to Ventricular Tachycardia in a Murine Model of Oculodentodigital Dysplasia
Authors: Nellie Kalcheva, Zhiyong Wang, Nefthi Sandeep, Glenn I Fishman
Journal: Circulation (2006)

Mutations in the gene encoding connexin43 (Cx43), have been identified in families with oculodentodigital dysplasia (ODDD), a dominantly inherited disorder with pleiotropic phenotypic manifestations. In one family with ODDD due to an isoleucine to threonine missense mutation at residue 130 (I130T), several individuals developed cardiac rhythm disturbances including ventricular tachycardia and sudden cardiac death. To explore the molecular pathology linking Cx43 mutations with arrhythmic behavior, we established a murine model of ODDD by introducing the disease causing I130T mutation into the Cx43 gene through homologous recombination. Approximately 20% of heterozygous Cx43-I130T mutant mice died in the immediate perinatal period, whereas the other 80% have survived for at least 5 months. Heterozygous mutant mice develop hindlimb syndactyly - a common phenotypic characteristic of humans with ODDD. The hearts of mutant mice did not display gross anatomical abnormalities and evaluation of left ventricular chamber size, wall thickness and contractile performance as assessed by echocardiography was not significantly different than wildtype littermates. Western blot analysis of heterozygous I130T mice demonstrated substantially less than 50% of wildtype levels of Cx43, whereas Cx43 transcript levels were normal, suggesting a dominant-negative effect of the mutation on Cx43 protein stability. Immunohistochemical stainining demonstrated less efficient trafficking of Cx43 to the intercaled disk in mutant hearts. Optical mapping studies of impulse propagation in Langendorff-perfused hearts demonstrated significant slowing (p&lt;0.05) of conduction velocity in both the longitudinal (.61 ± .03 m/s vs .74 ± .04 m/s) and transverse (.30 ± .02 m/s vs .43 ± .02) directions in mutant hearts compared to wildtype littermates. Moreover 7/7 mutant hearts developed spontaneous and inducible sustained monomorphic ventricular tachycardia where 0/7 wildtype littermates developed sustained arrhythmias. In summary, Cx43-I130T mutant mice display phenotypic features of human ODDD including syndactyly and rhythm disturbances. Additional study of this novel mouse model will provide insights into aberrant function of Cx43 and pro-arrhythmic behavior.
Abstract 5254: The Role of Caveolae on the Inhibition of Coronary Arterial BK Channels by Angiotensin II in Control and Diabetic Rats
Authors: Tong Lu, Daimin Zhang, Xiao-Li Wang, Tongrong He, Zvonimir S Katusic, Hon-Chi Lee
Journal: Circulation (2009)

Background: We have found that the vascular large conductance Ca 2+ -activated K + channels (BK) are targeted to caveolae. The goal of this study is to determine the role of caveolae in BK regulation by angiotensin II (AII) in normal and diabetic rats. Results: In coronary arterial smooth muscle cells (CASMC) from control rats, AII (2 μ M) inhibited BK by 40.5% from 227±26 pA/pF to 135±14 pA/pF (HP −60 mV, TP 150 mV, n=7, p&lt;0.05). However, AII had no effects on BK in CASMC transfected with caveolin-1 siRNA (vs 50% inhibition in cells transfected with control siRNA) or in cells from Cav1−/− mice, suggesting the AII effects are caveolae-dependent. Density gradient analysis of rat vessel homogenates showed that caveolin-1, BK, Gq, cSrc, and NOX-1 all reside in the caveolae-rich fraction, where AT 1 R was absent unless the animal was pre-treated with AII, suggesting receptor translocation upon agonist activation. However, CASMC from streptozotocin-induced diabetic rats showed significant reduction in BK (61.5±10.6 pA/pF) with no response to AII (61.2±15.7 pA/pF, n=8). Vascular BK, caveolin-1, AT 1 R, cSrc, and NOX-1 expression in caveolae were all upregulated by 1.6- to 3.1-fold in diabetes. Density gradient analysis of diabetic vessels showed the presence of AT 1 R in the caveolae-rich fraction without AII pretreatment, suggesting that the AT 1 R signaling pathway might be constitutively active in diabetes. This was accompanied by a 2-fold increase in BK tyrosine phosphorylation and BK tyrosine nitration. The AII effects on BK function in diabetic CASMC were abolished by pretreatment (1 hr) with PKC inhibitor or by LavA (cSrc inhibitor) and can be mimicked by incubation (2 hr) of control CASMC with peroxynitrite. Conclusion: AT 1 R-BK-enzyme complex in the caveolae microdomain is critical in vascular BK regulation. Enhanced AII-signaling facilitates BK post-translational modification, resulting in BK dysfunction in diabetes.
Abstract 5262: Progressive Decline in C-Type Natriuretic Peptide With Aging is Associated With Cardiorenal Fibrosis, Myocardial Dysfunction and Proteinuria
Authors: S. Jeson Sangaralingham, Fernando L Martin, Tomoko Ichiki, Paul M McKie, Selma F Mohammed, Gerald E Harders, Elise A Oehler, Horng H Chen, Margaret M Redfield, John C Burnett
Journal: Circulation (2009)

Background: C-type natriuretic peptide (CNP) is of endothelial cell origin and represents the most potent anti-fibrotic peptide of the natriuretic peptide family and is important for extracellular matrix homeostasis including mediating bone growth in the young. Cardiorenal aging is associated with altered cardiac and renal structure and function that may contribute to the development of heart and kidney failure, particularly in the elderly. The impact of aging on circulating CNP and associated changes in cardiorenal structure and function are undefined. Hypothesis: We hypothesized that a decrease in endogenous plasma CNP occurs with aging and is associated with an increase in cardiorenal fibrosis and altered left ventricular (LV) and renal structure and function. Methods: Studies were performed in 2, 11 and 20 month old male Fischer rats (n = 8 –10/group). Echo was used to assess LV structure and function. Blood pressure (BP), urinary protein excretion, plasma B-type natriuretic peptide (BNP) and CNP were measured. Kidneys and LV were harvested for gross and histology analysis. Mean±SE, *p&lt;0.05. Results: Aging from 2 to 20 months was associated with progressive reductions in plasma CNP (30±3 to 21±1* to 9±1*pg/ml). Significant and progressive cardiac and renal fibrosis were observed with aging (LV: 9±0.3 to 15±0.7* to 21±1*% and kidney: 1±0.3 to 8±2* to 17±1* %). In contrast to CNP, plasma BNP was modestly increased from the 2 to 20 month old group (21±2 to 26±1*pg/ml). The reduction in CNP and increase in BNP, the latter a biomarker for LV dysfunction, were associated with decreased EF (88±1 to 80±1*%) and increased LVEDd (6.61±0.09 to 7.48±0.09*mm). BP and urinary protein excretion were mildly elevated with aging (91±1 to 101±3* mmHg and 8±0.3 to 20±3* mg/day, respectively). Conclusion: We report for the first time that aging is associated with a progressive decline in circulating CNP and progressive cardiorenal fibrosis, systolic dysfunction and proteinuria. Further studies are warranted to explore the hypothesis that a mechanism of cardiorenal aging with altered cardiorenal structure and function may include a decrease in the bioavailability of CNP.
Abstract 585: Activated Vitamin D Attenuates Left Ventricular Hypertrophy and Dysfunction in DAHL Salt-Sensitive Rats
Authors: Natalya Bodyak, Juan Carlos Ayus, Venkatesha Shivalingappa, Debra Rigor, Yee-Shiuan Chen, Quingen Ke, Ananth Karumanchi, Ravi Thadhani, Peter M Kang
Journal: Circulation (2006)

Introduction: Cardiovascular disease is the leading cause of death among end-stage renal disease (ESRD) patients. Paricalcitrol (PC), an activated vitamin D analog, is associated with improved survival in patients with ESRD. The mechanism of improved mortality, however, is unclear. We hypothesized that administration of PC would attenuate the development of cardiac dysfunction in Dahl salt sensitive (DSS) rats following a high salt (HS) diet, and improve cardiac structure and function in ESRD patients. Methods: Male DSS rats were fed a HS diet (6% NaCl) for 6 weeks beginning at 6 wk of age. PC was administered IP at 200 ng 3x/wk. Animals were evaluated for cardiac function, hemodynamics, mRNA expression of ANF, and plasma BNP levels. Also, a cohort of 77 ESRD patients treated with PC and followed for one year was examined for cardiac function by echocardiogram. Results: Rats on HS + PC compared with HS + vehicle developed significant decrease in heart weight/body weight (HW/BW) ratio (29%, p&lt;0.05) and lung weight/body weight (LW/BW) ratio (27 %, p&lt;0.05). Echocardiogram analysis revealed that PC treatment lead to significant improvement of fractional shortening compared with HS + vehicle treated animals (52.9±1.0 % vs. 45.7±1.6 %, p&lt;0.05). Furthermore, LV pressure measurement showed that PC treatment resulted in significant improvement of LV end diastolic pressure (46%, p&lt;0.05). In addition, significant increase in plasma BNP level was attenuated by PC treatment (67% reduction, p&lt;0.05). PC treatment also significantly attenuated HS diet induced ANF mRNA increase. PC, however, did not have significant change in mean arterial pressure suggesting that beneficial effect seen by PC is not due to lowering of hypertension. In humans, twelve month echo changes in ESRD patients demonstrated that an improvement in E/A ratio and ejection fraction was associated with increasing dose of PC (p&lt;0.05). Conclusion: Administration of PC 3x/week attenuated the development of LVH and LV dysfunction in high salt-induced cardiac hypertrophy and cardiac dysfunction in DSS rats. This finding may also be present in ESRD patients, but these findings remain observational and require confirmation.