tbuckley/cabot-search huggingface dataset:
Abstract 4917: Peptide-based Antibodies Against Glutathione-binding Domains Suppress Superoxide Production Mediated by Mitochondrial Complex I
Authors: Jingfeng Chen, Chwen-Lih Chen, Chun-An Chen, Pravin P Kaumaya, Jay L Zweier, Yeong-Renn Chen
Journal: Circulation (2009)

Complex I (NQR) is a critical site of superoxide (O 2 •− ) production and the major host of reactive/regulatory protein thiols in mitochondria. In response to oxidative stress, NQR-derived protein thiols at the 51 kDa and 75 kDa subunits are known to be reversibly S-glutathiolated. Although several glutathiolated domains from NQR 51 kDa and 75 kDa have been identified, their role in the catalytic and regulatory function remain to be determined. To gain further insights into protein S-glutathiolation of complex I in myocardial ischemia and reperfusion, we used two S-glutathiolated peptides ( 200 GAGAYI C206 GEETALIESIEGK 219 of 51-kDa protein and 361 VDSDTL C367 TEEVFPTAGAGTDLR 382 of 75-kDa protein) as chimeric epitopes incorporating a “promiscuous” T cell epitope to generate two polyclonal antibodies, AbGSC206 and AbGSC367. Binding of AbGSC206 and AbGSC367 inhibited NQR-mediated O 2 •− generation by 37% and 57%, as measured by EPR spin-trapping with DEPMPO. To further provide an appropriate control, two non-glutathiolated peptides ( 21 SGDTTAPKKTSFGSLKDFDR 40 of 51-kDa and 100 WNILTNSEKTKKAREGVMEFL 120 of 75-kDa) were synthesized as chimeric epitopes to generate two high titer polyclonal antibodies, Ab51 and Ab75. Binding of A51 did not affect NQR-mediated O 2 •− generation. However, binding of A75 inhibited NQR-mediated O 2 •− generation by 35%. None of AbGSC206, AbGSC367, Ab51, or Ab75 showed an inhibitory effect on the electron transfer activity of NQR, suggesting that antibody binding to the GS-binding domain decreased electron leakage for superoxide generation mediated by complex I. Purified Ab51 and Ab75 showed high immunological specificity to the NQR of rat myocardial tissue and the mouse cardiac myocyte HL-1 cell line. Rats were subjected to 30 min of coronary ligation followed by 24 hours of reperfusion. When tissue homogenates were immunoprecipitated with Ab51 or Ab75 and probed with an antibody against glutathione, protein S-glutathiolation was enhanced by 60.8±5.7% ( p &lt; 0.05, n = 6) in the post-ischemic myocardium at the NQR 51 kDa subunit, but not significantly changed at the NQR 75 kDa subunit, suggesting that the NQR 51 kDa subunit is more sensitive to oxidative stress caused by myocardial infarction.
Abstract 5441: Critical Role of Increased MicroRNA-126 Expression for the Pro-angiogenic Capacity of Autologous Human CD34+ Stem/Progenitor Cells
Authors: Pavani Mocharla, Sylvie Briand, Giovanna Giannotti, Carola Doerries, Thomas F Lüscher, Ulf Landmesser
Journal: Circulation (2009)

Circulating, bone-marrow derived CD34+ progenitor cells have been shown to promote ischemia-induced neovascularisation, and are currently explored as a potential novel therapeutic strategy in ischemic heart disease. By using culture approaches “early” endothelial progenitor cells (EPCs) are thought to be derived from CD34+/CD14+ cells, whereas “late outgrowth” EPCs are thought to be derived from CD34+/CD14− cells. The aim of the present study was to determine the expression of pro- and anti-angiogenic microRNAs in CD34+ cells and to characterize their role for endothelial growth promoting effects. Methods: We examined the pro- and anti-angiogenic microRNA expression profile, of circulating CD34+14+ and CD34+14− stem/progenitor cells, as compared to CD34−14+ (monocytes) and CD34−14− (lymphocytes) isolated by MACS sorting from mononuclear cells, by using quantitative RT-PCR. Furthermore, pro-angiogenic effects of these cell populations were examined by tubulogenesis in co-cultures with differentiated endothelial cells (HAECs). In vivo endothelial repair capacity was determined by cell transplantation (200,000 cells) into nude mice with carotid endothelial injury. The functional role of differentially regulated miRs was characterized by transfection with anti-miRs and miR mimics. Results: Only CD34+14+ and CD34+14−, but not CD34−14+ or CD34−14− cells exerted a pro-angiogenic effect, paralleled by a substantially increased expression of the pro-angiogenic miR126 and miR130a. Similarly, in vivo endothelial repair was enhanced by CD34+ cells with no significant difference between CD34+14+ and CD34+14− cells. CD34+ cell transfection with anti-miR-126 abolished the pro-angiogenic effects of CD34+ cells, whereas forced expression of miR126 (miR mimic) markedly enhanced their pro-angiogenic effects. Conclusions: These findings demonstrate for the first time a differential pro-angiogenic microRNA expression of CD34+ stem/progenitor cells as compared to CD34− mononuclear cells. Importantly expression of miR126 is critical for endothelial growth promoting effects of CD34+ cells, and represents an interesting novel target to enhance the pro-angiogenic capacity of autologous CD34+ stem/progenitor cells.
Abstract 4850: Improved Myocardial Energetics Following Chronic Treatment Using an Implantable Device in Resistant Hypertension: Results From European and United States Trials of the Rheos <sup>®</sup> System
Authors: Peter de Leeuw, John D Bisognano, David S Bach, Eric G Lovett, Christopher L Kaufman
Journal: Circulation (2009)

Background: The Rheos System provides Baroreflex Activation Therapy (BAT ™ ) and has been shown to chronically reduce blood pressure and improve left ventricular (LV) structure and function in patients with resistant hypertension (HTN). The effect of BAT on myocardial energetics and mechanical efficiency is unknown. Methods: Resistant HTN (stage II) patients (systolic BP ≥160 mmHg) taking ≥3 anti-HTN drugs were implanted with the Rheos System which was activated 1 month after implant. Baseline data were acquired before implant. Follow-up echocardiograms were performed after 3 and 12 months of BAT. Echocardiograms were reviewed at a blinded core lab. Stroke work was calculated as systolic BP × stroke volume × 0.0144 and eMVO 2 was defined as heart rate × systolic BP. Myocardial mechanical efficiency was defined as the ratio of stroke work/eMVO 2 . Changes at follow-up vs. pre-implant were analyzed with paired t-tests. Data are presented as mean ± SEM. Results: 34 subjects (19 M/15 F, Age 52.5±1.8 yr) were implanted at 8 centers. Pre-implant myocardial mechanical efficiency was normal. A 15% reduction in stroke work was observed at 3 months and was sustained after 12 months of BAT despite a reduction in anti-HTN medications (table ). eMVO 2 was significantly reduced with BAT. Myocardial mechanical efficiency was preserved. Cardiac structure, as indexed by LV mass index and left atrial dimension, was abnormal at pre-implant but was significantly improved after BAT. Conclusions: In addition to previously documented blood pressure reduction, chronic BAT improves myocardial energetics, as indicated by reduced stroke work and eMVO 2 , while maintaining normal myocardial efficiency in resistant hypertensive patients. Concomitant improvements in cardiac structure were also observed. These data suggest that BAT provide benefits beyond blood pressure reduction and are under further investigation in a large placebo-controlled clinical trial. Changes in Cardiac Function and Structure &amp; Medication with BAT
Delivery of SOD With Polyketal Particles Protects Rats From Acute Myocardial Infarction
Authors: Michael E Davis
Journal: Circulation (2009)

Abstract #3086 Michael E Davis, Gokulakrishnan Seshadri, Sergey Dikalov, Milton Brown, Emory Univ Sch of Med, Atlanta, GA; Niren Murthy, Georgia Inst of Technology, Atlanta, GA Michael E Davis, 2009 Finalist and Presenting Author
Abstract 4895: Competing Effects of Hypokalemia and Hydrochlorothiazide Treatment on Regression of Cornell Product Left Ventricular Hypertrophy in Hypertensive Patients: Implications for Development of Potassium-Sparing Diuretics
Authors: Peter M Okin, Sverre Kjeldsen, Lars H Lindholm, Björn Dahlöf, Richard B Devereux
Journal: Circulation (2009)

Background: Hydrochlorothiazide (HCTZ) treatment is associated with blood pressure reduction and regression of left ventricular hypertrophy (LVH). HCTZ is also associated with hypokalemia (hypoK), which increases blood pressure and is associated with a greater likelihood and severity of electrocardiographic (ECG) LVH. However, the competing effects of HCTZ use and concomitant hypoK on LVH regression have not been examined. Methods: Baseline and yearly Cornell product (CP) ECG LVH levels were examined in relation to hypoK (serum K ≤ 3.90, the lowest quartile) and HCTZ use in 7816 patients in the LIFE study with baseline and year-1 K levels. Patients were randomized to losartan vs atenolol-based treatment and additional HCTZ as needed. Results: Patients on HCTZ had lower serum K levels at year 1 (4.05 ± 0.38 vs 4.24 ± 0.38), year 2 (4.04 ± 0.38 vs 4.25 ± 0.38), year 3 (4.04 ± 0.39 vs 4.27 ± 0.39) and year 4 (4.05 ± 0.41 vs 4.26 ± 0.38) of the study (all p &lt; 0.001). In 2-way analysis of covariance adjusting for age, sex, race, prior and randomized treatment, yearly body mass index, serum glucose and creatinine, and for baseline and change in diastolic and systolic pressure, hypoK was associated with less mean reduction of CP LVH whereas HCTZ use was associated with greater regression of CP LVH between baseline and years 1 to 4. Multivariate logistic regression analyses with the same covariates revealed that hypoK was associated with a statistically significant 15 to 19% lower likelihood of ≥ median (236 mm·ms) reduction in CP LVH while HCTZ use was associated with an 18 to 33% greater likelihood of CP LVH regression of ≥ 236 mm·ms between baseline and years 1 to 4. Conclusions: HCTZ therapy is independently associated with a greater likelihood and magnitude of LVH regression whereas concomitant hypoK is associated with a competing lower likelihood and magnitude of LVH regression during antihypertensive therapy. These findings suggest that hypoK may blunt regression of LVH during treatment. Regression of Cornell Product LVH in Relation to HCTZ Use and Hypokalemia
Abstract 5090: Nadph Oxidase-mediated Arterial Dysfunction in Patients With Peripheral Arterial Disease
Authors: Lorenzo Loffredo, Roberto Carnevale, Roberto Cangemi, Ludovica Perri, Serena Di Santo, Paola Mormina, Stefania Basili, Pasquale Pignatelli, Francesco Violi
Journal: Circulation (2009)

BACKGROUND. Peripheral arterial disease (PAD) is a clinical setting characterized by endothelial dysfunction and atherosclerosis. NADPH oxidase is believed to modulate arterial tone and oxidative stress but its role in PAD is still unclear. OBJECTIVE. The aim of this study was to evaluate whether NADPH oxidase is implicated in determining reduced FMD and to assess if the administration of an antioxidant was able to improve arterial dilatation and gp91phox, the catalytic core of NADPH oxidase, serum levels in PAD patients. METHODS. We performed a cross-sectional study comparing flow-mediated dilation, oxidative stress, by serum levels of 8-Hydroxy-2-deoxy-2-deoxyguanosine (8-OHdG), and NO generation, by serum levels of nitrite/nitrate (NOx), and serum gp91phox in a population of PAD patients (n=25; mean age: 63.7±7.9 years) and controls (n=40; mean age: 64.2±11.2 years). In the second part, we performed an interventional cross-over study in PAD patients to assess if the infusion of an antioxidant, propionyl-L-carnitine (PLC), vs placebo, was able to improve endothelial dysfunction and serum gp91phox levels in 20 PAD patients. RESULTS. Compared with controls, patients with PAD had enhanced gp91phox (mean±S.E.: 21.3±3.6 vs 71.7±14; p&lt;0.001) and 8-OHdG serum levels (mean±SD: 2.4+1.2 vs. 4.24+3.11 ng/mL; P&lt;0.001), reduced NOx (mean±SD:17.02+6.11 vs.11.28+6.02 mM; P&lt;0.001), and lowered FMD (mean±SD: 10.34+2.14 vs. 6.69+2.95%; P&lt;0.001). General linear model analysis for repeated measures showed that PLC infusion was associated with an increase of FMD (from 6.6±0.6 to 11.1±1.2%, F=9.98, p=0.005) and with a reduction of serum gp91phox (from 88.2±13 to 38.6±5.9, F=9.98, p=0.006). No changes were observed after placebo treatment. CONCLUSIONS. This study shows that in PAD patients, gp91phox is overexpressed and may contribute to reduce FMD.
Abstract 4926: Tyrosine Kinase Inhibitors Are Potent Pulmonary Vasodilators in Rats
Authors: Kohtaro Abe, Masako Ito, William T Gerthoffer, Karen A Fagan, Ivan F McMurtry, Masahiko Oka
Journal: Circulation (2009)

Background: The pathogenesis of pulmonary arterial hypertension (PAH) includes vascular remodeling and vasoconstriction. Tyrosine kinase inhibitors have recently been reported promising for the treatment of PAH. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases, such as platelet-derived growth factor receptor, and subsequent attenuation of vascular remodeling. Nothing, however, has been considered regarding their potential vasodilatory activity. This study examined whether tyrosine kinase inhibitors might acutely induce pulmonary vasodilation. Methods and Results: In isolated extra-lobar pulmonary arteries from normal adult rats, imatinib, sorafenib, and nilotinib concentration-dependently reversed U46619-induced contractions (see figure ). Nitro-L-arginine did not reduce their relaxant potency. Imatinib (30 uM) reduced phosphorylation of MYPT-1 in U46619-treated arterial rings. Imatinib (50 mg/kg, ip) acutely and preferentially lowered high right ventricular systolic pressure (from 96 ± 11 to 67 ± 7 mmHg, a 29 % reduction) compared to systemic arterial pressure (from 98 ± 3 to 89 ± 5 mmHg, a 10 % reduction) in SUGEN 5416 (VEGF receptor inhibitor; 20 mg/kg, sc) plus chronic hypoxia-exposed severe pulmonary hypertensive rats. Conclusion: Tyrosine kinase inhibitors have potent, Ca2+ desensitization-dependent pulmonary vasodilator activity, which could be involved in their long-term beneficial effect against PAH.
Abstract 5261: Myocardial Infarction Impairs Renal Function, Induces Renal Interstitial Fibrosis and Increases Kim-1 Expression: Implications for the Cardiorenal Syndrome
Authors: Suree Lekawanvijit, Andrew Kompa, Yuan Zhang, Bing H Wang, Darren J Kelly, Henry Krum
Journal: Circulation (2009)

Introduction: Accelerated progressive decline in renal function has been described as a coexistent event post-myocardial infarction (MI) (cardiorenal syndrome, CRS). We hypothesized that MI has early detrimental effects on the kidney by evaluating functional, structural and molecular changes over time. Methods: Male Sprague-Dawley rats were randomized to three groups: non-operated, sham and MI. Cardiac and renal function was assessed prior to sacrifice at 4, 8, 12 and 16 weeks. Tissues were assessed for injury markers and pathological changes using histological methods and real-time PCR. Results: Myocardial infarct size and blood pressure (BP) were the same in all groups. Percent fractional shortening was reduced in MI animals at all time points by up to 63% at 16 weeks. As expected, heart/body weight (BW) and left ventricle/BW were significantly greater in MI than sham animals. Glomerular filtration rate (GFR) was significantly decreased in MI compared to sham at 4 wks ( p =0.016) but not at 8 and 12 wks; and deteriorated further at 16 wks ( p =0.052). Renal cortical interstitial fibrosis and TGF- β bioactivity (p-smad2) were significantly greater in MI animals at all time points. The degree of fibrosis progressively increased and was maximal at 16 weeks. TGF- β 1 gene expression in the kidney cortex trended toward an increase at 4 and 8 weeks ( p =0.109 and 0.070, respectively). In addition, Kim-1 positive staining in the tubules was more prominent in MI animals over time. Conclusions: CRS occurs early post-MI and is associated with progressive renal interstitial fibrosis via activation of Smad2 signaling pathway. Kim-1 may represent an early marker of post-MI kidney injury.
Abstract 4841: The Impact of Chronic Uremia on Ichemic Preconditioning of the Myocardium
Authors: Kieran Mccafferty, Conor Byrne, Julius Kieswich, Magdi Yaqoob
Journal: Circulation (2009)

Background Ischemic Preconditioning (IPC) is a process by which brief non lethal periods of ischemia render the dependant tissue resistant to subsequent lethal injury. This process has been extensively studied in animal models and this has led to human clinical trials. There is evidence to suggest that additional co-morbidities may render hearts more resistant to the effects of IPC. There is no published data examining the effects of chronic uraemia on IPC. This is of clinical importance due to the burden of cardiovascular disease in CKD patients. Hypothesises Can uremic hearts respond to an IPC stimulus Can uremic hearts respond to an IPC stimulus as well as non uremic hearts Methods The 5/6 nephrectomy model (SNx) in male Wistar rats was used as a model of chronic uraemia. We performed 2 experiments to test the hypothesises. Expt 1: SNx rats were divided into 2 groups. The control group (n=15) underwent myocardial ischemia using reversible LAD artery ligation. The LAD was occluded for 25 minutes and reperfused for 2 hours. The IPC group (n=4) had 3 cycles of 5 minutes LAD ligation and 5 minutes reperfusion followed by 25 min occlusion and 120min reperfusion. Expt 2: SNX animals (n=8) and Sham controls (n=6) underwent x1 cycle of IPC as above with 35minutes ischemia 2 hours reperfusion. At the end of the experiment the animals were sacrificed and the infarct size was measured and expressed as a percentage of the area at risk (AAR). Results Expt 1: Median Infarct size was 61.2% and 7.5% in the control and IPC groups respectively (P=0.003) Expt 2: Median infarct size was 16.8% and 43.7% in the SNX and sham SNx groups respectively. (P=0.008) The AAR was not significantly different in any of the groups studied. Discussion This is the first evidence that unlike ‘old’ hypertensive rats and diabetic rats, uremic rats can respond to a preconditioning stimulus. Furthermore it appears that the preconditioning may confer greater protection in uremic animals than controls. We hypothesize that the significantly lower haemoglobin in the uremic animals reduces microvascular occlusion which may occur during IPC. Work is underway to quantify this finding. Conclusion This study suggests that clinical trials using IPC in uremic patients could improve outcomes following cardiac interventions.
Abstract 4870: Mechanisms Leading to Impaired Endothelial-vasoprotective Properties of High Density Lipoprotein (HDL) in Patients With Coronary Disease (CAD)
Authors: Christian Besler, Kathrin Heinrich, Lucia Rohrer, Keiko Yonekawa, Carola Doerries, Costantina Manes, Maja Müller, Christian Templin, Roberto Corti, Willibald Maier, Christophe Wyss, Jasmina Alibegovic, Nils Kucher, Arnold von Eckardstein, Thomas F Luscher, Ulf Landmesser
Journal: Circulation (2009)

Background: HDL-raising therapies are currently intensely evaluated as a potential novel therapeutic strategy in patients with CAD. However, vascular effects of HDL have been observed to be highly variable. The aim of the present study was therefore to characterize mechanisms leading to altered endothelial-vasoprotective properties of HDL in patients with CAD. Methods: HDL was isolated from patients with stable CAD (sCAD), an acute coronary syndrome (ACS) and healthy subjects (HS; n=20 –25) by sequential ultracentrifugation. The effects of HDL on endothelial nitric oxide (NO) production, endothelium-dependent, NO-mediated vasodilation, signaling pathways leading to eNOS activation and endothelial superoxide production (ESR spectroscopy analysis) were examined. HDL-associated paraoxonase (PON) activity/content and endothelial binding of HDL (radioactive 125I-labelling of HDL) were characterized. Moreover, the role of eNOS and PON for anti-inflammatory properties of HDL were determined. Results: HDL from HS, but not HDL from sCAD/ACS patients, potently stimulated endothelial NO production. HDL from HS increased endothelial Akt, eNOS-Ser1177-phosphorylation and eNOS-Thr495-dephosphorylation, that was not observed with HDL from sCAD/ACS patients. Endothelial binding capacity of HDL was markedly reduced in patients with CAD. PON activity was reduced (−62.2% and −70.4% vs. HS, P&lt;0.001), whereas PON1 content was increased in HDL from sCAD/ACS patients as compared to HDL from HS, suggesting inactivation of HDL-associated PON in CAD. Inhibition of PON activity prevented the capacity of HDL from HS to stimulate Akt/eNOS phosphorylation, endothelial NO production, NO-dependent vasodilation and to exert anti-inflammatory effects. eNOS siRNA knockdown prevented anti-inflammatory effects of HDL from HS. Conclusion: The present study demonstrates that reduced endothelial binding of HDL and inactivation of HDL-associated paraoxonase are major mechanisms leading to impaired endothelial-vasoprotective and anti-inflammatory effects of HDL in CAD patients. HDL-targeted treatment approaches should therefore not only increase HDL levels, but likely more important, restore endothelial-vasoprotective properties of HDL.
Abstract 5256: Increased Endothelin-A Receptor-Protein Expression/Localization and Contractile Response to Endothelin-1 of Coronary Microvasculature From Diabetic Patients
Authors: Yuhong Liu, Jun Feng, Kamal Khabbaz, Robert Hagberg, Robina Matyal, Frank Sellke
Journal: Circulation (2009)

Objectives: Hyperglycemia is a potent stimulus for endothelin-1 (ET-1) production. Increased ET-1 exposure of coronary vasculature and myocytes in diabetics can hamper blood flow delivery to the vulnerable myocardium and exacerbate contractile function. In the present study, we investigated the protein expression/localization of ET-A receptors, the contractile response to ET-1 and the inhibition of ET-A receptors in the human coronary microvasculature in diabetic and case-matched non-diabetic patients. Methods: Right discarded atrial tissues were harvested pre-CPB from 30 patients with and without diabetics undergoing cardiac surgery. Coronary arterioles (90 – 180 micrometer in diameter) were dissected from the harvested tissue and placed in an organ bath containing Krebs solution. Microvascular constriction was assessed by videomicroscopy in response to ET-1, with and without an endothelin-A (ET-A) receptor antagonist. The expression and localization of ET-A receptors were also examined using immunoblot and confocal immunofluorescence microscopy. Results: ET-1 caused a dose-dependent contractile response of coronary arterioles from diabetics and non-diabetics. The contractile response of diabetic arterioles to ET-1 (10 −9 M) was significantly increased compared with those of non-diabetics (15±3% vs. 8±2%, P&lt;0.05). The contractile response of microvessels from diabetics and non-diabetics to ET-1 was significantly inhibited in the presence of the ET-A receptor antagonist BQ123 (10 −7 M, P&lt;0.05, respectively). The protein expression of ET-A receptors was significantly elevated from 1 fold of non-diabetics to 2.5 folds of diabetics (P&lt;0.01). Immunofluorescent staining displayed stronger ET-A receptors signals of smooth muscle from diabetics than those of non-diabetics. Conclusion: Hyperglycemia up-regulates ET-A-receptor protein expression/localization and increases the contractile response to ET-1 in the diabetic coronary microvasculature. The contractile response to ET-1 is via activation of ET-A receptors in diabetics since blockade of ET-A receptors prevented ET-1-induced vasoconstriction. These findings support the notion that diabetic patients face an increased ET over-stimulation.