tbuckley/cabot-search huggingface dataset:
Abstract 5210: Redox Regulation of ATP-sensitive Potassium Channels: A Possible Role for Thioredoxins
Authors: Li Bao, Diane Delaroche, Brian Malester, William Coetzee
Journal: Circulation (2009)

Cardiac ATP-sensitive potassium (K ATP ) channels are gated by intracellular nucleotides, which link energy metabolism to membrane excitability and consequent contractility. However, there is an increasing realization that the K ATP channel is also under the control of other associated proteins belonging to channel megadalton complex. Using bioinformatic approaches we identified a possible coiled-coil (CC) domain in SUR subunits. To identify proteins that associate with SUR subunits, we used this CC-domain as the bait in a two-hybrid screen against a rat cardiac cDNA library and identified thioredoxin 2 (Trx2) as a putative candidate. We confirmed interaction between Trx2 and the SUR CC-domain using GST pull-down assays. In a heterologous expression system we further demonstrated using co-immunoprecipitation assays that both forms of thioredoxin (Trx1 and Trx2) interact with full-length SUR1 or SUR2. Immunoprecipitation of SUR1 from MIN6 cells was followed by mass spectrometry, which confirmed that Trx1 natively associates with SUR1 subunits. Given that thioredoxins act as antioxidants to reduce proteins by cysteine thiol-disulfide exchange, our data suggest that K ATP channel activity is likely regulated by redox state. To examine this hypothesis, we assessed the effects of oxidation with hydrogen peroxide (H 2 O 2 ; 10 μ M to 1.5 mM) on the activity of K ATP channels (Kir6.2/SUR1) expressed in CHO cells using patch clamp techniques. H 2 O 2 had no effect on K ATP channels in the absence of ATP. When channels were partially blocked by sub-maximal levels of ATP (10 μ M to 1 mM), H 2 O 2 dose-dependently increased channel activity. Interestingly, low H 2 O 2 concentrations (10 to 30 μ M) transiently activated K ATP channels, whereas higher concentrations (&gt;300 μ M) caused a sustained activation. H 2 O 2 decreased the channel sensitivity to ATP (IC 50 8.9±0.26 vs. 21.7±0.15 uM; n = 9 –10) and had no effect on MgADP sensitivity. Our data demonstrate that oxidation (which occurs with ischemia/reperfusion) activates K ATP channels and suggest that thioredoxins, as components of the K ATP channel macromolecular complex, may regulate its response to cellular redox state.
Abstract 5155: Superoxide-Dependent Cathepsin Activation System is Associated with Hypertensive Renal Remodeling and Represents a Target for Statin
Authors: Xian Wu Cheng, Kenji Okumura, Takeshi Sasaki, Kazumasa Unno, Hideo Izawa, Akihiro Hirashiki, Kohzo Nagata, Masafumi Kuzuya, Mitsuhiro Yokota, Toyoaki Murohara
Journal: Circulation (2009)

Objective: Cathepsins are members of the cysteine protease family that participate in various types of tissue remodeling. Given that NADPH oxidase is implicated in protease activation, we examined the possible role of NADPH oxidase-dependent cathepsin activation in hypertensive renal remodeling with heart failure (HF) in Dahl salt-sensitive (DS) rats. Methods and Results: DS rats maintained on a high-salt diet were randomly assigned to four groups (( n = 10 for each group) that were treated with either vehicle (0.5% carboxymethyl cellulose; CMC), low-dose pitavastatin (1 mg/kg/d; Pitava-L), high-dose pitavastatin (3 mg/kg/d; Pitava-H), E64d (a cysteine protease inhibitor), or pitavastatin from 12 to 19 weeks of age. Rats fed a low-salt diet served as controls. Marked cortical mesangial matrix expansion and the levels of collagen type I and III, angiotensin II type receptor 1 (AT 1 R), and mineralocorticoid receptor (MR) mRNAs and the activity of cathepsin S and its protein in the kidney were increased in the CMC group with HF at 19 weeks compared with control rats. Immunostaining showed strong signaling for cathepsin S in the glomerular cells in the kidney of HF rats. Treatment with either dose of pitavastatin reduced the extent of fibrosis, the collagen type I and III mRNAs, and cathepsin S activity and its protein expression compared with those in CMC rats. The decrease in the ratio of reduced to oxidized glutathione and the increase in macrophage infiltration and NADPH oxidase activity as well as its subunits (including p22phox and gp91phox) and superoxide production apparent in the kidney of CMC rats were also inhibited by pitavastatin in a dose-dependent manner. These benefic effects of pitavastatin were partially mimicked by E64d and accompanied by amelioration of kidney fibrosis. Furthermore, both doses of pitavastatin reduced the levels of AT1R and MR mRNAs but not plasma angiotensin II levels. Conclusions: This is the first report showing that cathepsins are likely to trigger and promote kidney remodeling, and that pitavastatin suppresses the cathepsin activation system by the inhibiting NADPH oxidase-dependent superoxide anion production, leading to the prevention of kidney remodeling in hypertensive HF rats.
Abstract 4966: The High Mobility Group AT-hook 2 Gene Plays a Crucial Role in the Development of Aortic Rupture
Authors: Salah A. Mohamed, Anke Meyer, Isabel Stegen, Arlo Radtke, Doreen Richardt, Rolf Nimzyk, Vishal Nigam, Hans H. Sievers, Joern Bullerdiek, Gazanfer Belge
Journal: Circulation (2009)

Introduction The high mobility group AT-hook 2 ( HMGA2 ) gene has recently been shown to be a transcriptional organizer of transforming growth factor (TGF-β) signaling. It is proposed that HMGA2 acts in a gene-specific manner to regulate factors involved in epithelial-mesenchymal-transition (EMT), known to be expressed only during embryogenesis. We analyzed the expression profile of the HMGA2 gene in human aortic diseases. Methods and Results Aortic specimens were collected during surgery from 51 patients (mean age 56.8±15.3), 19 patients with acute aortic dissection (type A, 14m/5f), 26 samples obtained from aortic aneurysms (14 patients showed a bicuspid aortic valve, 12 patients tricuspid aortic valve), two Marfan syndrome samples, and aortic valves. Quantitative Real-Time-polymerase chain reaction (qRT-PCR) and immunohistochemical analysis were performed. The expression of let-7 microRNA, assumed to play a role in regulation of HMGA2 in cancer cells, was quantified and measured in fetal RNA. The HMGA2 gene was highly expressed in aortic type A dissection compared with all other samples (193.1 vs 8.7 fold, p = 2,4.10 −7 ). In fetal RNA, HMGA2 was expressed with 48-fold, however no significant expression of let-7 microRNA was detected among all investigated samples. Immunohistochemical investigation showed that HMGA2 protein was mainly detected in the endothelial cells of the vasa vasorum . Discussion The upregulation of HMGA2 in acute aortic dissection may indicate an involvement in the pathogenesis of rupture. HMGA2 protein was mainly restricted to cells of the vasa vasorum . It seems that HMGA2 -overexpression in aortic cells occurs in a let-7 independent manner, leading to increase angiogenesis of the vasa vasorum .
Abstract 5038: Enhanced Endothelial-specific Insulin Sensitivity Regulates Whole Body Glucose Homeostasis and Endothelial Function
Authors: Matthew Gage, Stephen Wheatcroft, Afroze Abbas, Helen Imrie, Richard Cubbon, Jessica Surr, Eleonore Dubois, Monique Jacoby, Stephane Schurmans, Mark Kearney
Journal: Circulation (2009)

Accumulating evidence now suggests that insulin resistance may promote atherosclerosis through a closely coupled association with endothelial dysfunction, and that the relationship between insulin resistance and endothelial function is reciprocal. However the role of the endothelium in whole body glucose regulation until now has remained unclear. SHIP2 is a lipid phosphatase which acts as a negative regulator of insulin signalling. In this study Cre-Lox technology is used to generate an endothelial-specific SHIP2 haploinsuffient mouse, as a model of enhanced endothelial-specific insulin sensitivity. We have investigated both the metabolic and vascular phenotype of this model to determine whether enhanced insulin signalling in endothelium modulates vascular function and whole body glucose regulation. Results described are from male EC-SHIP2 +/− offspring compared with control sex-matched littermates at 12–16 weeks of age. EC-SHIP +/− mice were morphologically indistinguishable from control littermates, exhibited normal development and body and organ masses were similar in both groups. No significant differences were observed in heart rate or blood pressure. Glucose tolerance after glucose challenge was found to be significantly better in EC-SHIP +/− than controls (p = &lt;0.05), with no differences in plasma insulin concentrations; fasted or after glucose challenge. Improved insulin sensitivity was confirmed in EC-SHIP +/− mice in insulin tolerance tests (p = &lt;0.05). e x vivo vasomotor studies in aorta revealed no significant differences between EC-SHIP +/− and controls in contractile responses to phenylephrine or maximal relaxation to sodium nitroprusside and ACh. However, basal phosphorylation of eNOS (Ser-1177) was greater in EC-SHIP +/− aorta than controls. In conclusion; the results suggest endothelial partial deletion of SHIP2 confers important effects on metabolic homeostasis and endothelial function. In particular, improved glucose tolerance and insulin sensitivity in EC-SHIP +/− mice support a critical role for insulin signalling in endothelial cells in whole body glucose regulation.
Abstract 4900: Left Ventricular Hypertrophy by Electrocardiography in the African-American Study of Kidney Disease and Hypertension
Authors: Louai Razzouk, Gail E Peterson, Jackson T Wright, Robert A Phillips, Tine L De Backer, David A Baran, Cynthia Kendrick, Tom Greene, Ricardo Esquitin, Ashish Aneja, Paul Muntner, Michael E Farkouh
Journal: Circulation (2009)

Purpose: Electrocardiogram (ECG) criteria for left ventricular hypertrophy (LVH) have low sensitivity in the general population though a high rate of ECG LVH has been consistently reported in African-Americans (AA). The purpose of the current study was to evaluate the value of ECG criteria among AA with hypertensive kidney disease, a population with a high burden of LVH. Methods: AA with hypertensive kidney disease (n = 645) were evaluated for LVH on echocardiography and ECG as part of the African-American Study of Kidney Disease and Hypertension (AASK) cohort. ECGs were read by two cardiologists at an independent core laboratory using the two Sokolow-Lyon criteria and the Cornell criteria. LVH on echocardiography was defined as left ventricular mass index &gt;49.2 and &gt;46.7 g/m 2.7 in men and women respectively, and was used as the gold standard. Results: The mean age of the patients was 60.1 years (SD = 10.1), 39.2% were women and 12.9% had diabetes. All patients had hypertensive kidney disease with a mean serum creatinine of 2.30 mg/dL (SD = 1.39). Sixty-nine percent of the population had LVH on echocardiogram, while 35% had LVH by any of the ECG criteria; 15% had LVH by Sokolow-Lyon-1 (S in V 1 + R in V 5 or V 6 whichever is larger &gt; 35 mm or R in V 5 or V 6 &gt;25mm), 16% by Sokolow-Lyon-2 (R in aVL &gt; = 11 mm) and 20% by Cornell criteria (S in V 3 + R in aVL &gt;28 mm in men, and S in V 3 + R in aVL &gt; 20 mm in women). LVH by ECG in AA had low sensitivity by any of the criteria, while specificity was higher (Table ). The NPV were low and PPV were higher regardless of the ECG criteria applied, and the kappa statistic indicated poor agreement between ECG- and echocardiogram-defined LVH. Conclusions: LVH by ECG had low sensitivity in this cohort of AA with hypertensive kidney disease. These results are consistent with previous findings from Caucasian and AA populations without chronic kidney disease.
2006 Distinguished Scientist Lecture—Insights Provided by Framingham Population Research
Authors: William B. Kannel
Journal: Circulation (2006)

The Framingham Study established the utility of population-based research for seeking out correctable predisposing conditions for cardiovascular disease (CVD), putting prevention at the forefront of cardiology. It established the risk factor concept of CVD evolution, recognizing that there is no single cause that is essential or sufficient by itself for CVD occurrence. It demonstrated the importance of distinguishing between usual (average) and optimal risk factor levels. It corrected clinical misconceptions about vascular disease, including: the hazard of atrial fibrillation; the relevance of diabetes as a macrovascular threat; the significance of left ventricular hypertrophy and small amounts of proteinuria; and the role of obesity, weight gain, and physical activity. Framingham investigation dispelled the concept of “benign essential hypertension” and the greater importance of diastolic blood pressure. It determined the full clinical spectrum of CVD, including sudden death, and silent coronary, stroke, and peripheral artery disease. The study determined CVD population incidence at a time when only mortality statistics were available, and now the lifetime risk. It quantified the hazard of a family history of CVD based on observations on parents and their offspring. The study provided insights on mechanisms of atherogenesis, including: LDL and HDL dyslipidemia, obesity-induced clustering of CVD risk factors, and smoking as a trigger for coronary attacks. It warned in 1985 of the lack of efficacy and danger of estrogen replacement for preventing CVD. The Framingham Study devised CVD risk profiles enabling physicians to pull together risk factor information to assess the global risk of heart attacks, failure, strokes, and peripheral artery disease. Findings of the study stimulated pharmaceutical industry development of agents for reducing blood pressure, lipids, glucose, and smoking, as well as trials demonstrating the efficacy of correcting risk factors. It also stimulated national campaigns against smoking, hypertension, hypercholesterolemia, and obesity.
Abstract 4872: Beta Blockers and Acute Release of ET-1 in Response to Anger Recall Stress in Patients With CAD
Authors: Hitender Jain, Matthew M Burg, Antonio B Fernandez, Margueritte White, Dorothea Collins, Robert Soufer
Journal: Circulation (2009)

Acute anger is associated with triggered AMI and transient myocardial ischemia. Anger provoked ischemia differs from demand related ischemia with regard to differential epicardial vs. microvascular processes. Use of beta-blockers is standard of care for patients with CAD. Endothelin-1 plays a central role in vascular regulation and homeostasis, particularly in diseased coronary segments, and has been linked to endothelial dysfunction during laboratory emotional stress. Beta-blockade has been reported to reduce plasma levels of ET-1 in patients with marked LV dysfunction/CHF and to inhibit the synthesis and release of ET-1 in cellular preparations. We studied the relationship of beta-blockade use on laboratory anger stress-provoked levels of ET-1 in patients with CAD without marked LV dysfunction/CHF. Methods and results: 104 patients with history of stable CAD underwent sequential 10-min resting baseline (BL) and 6 minute anger-recall stress (AR). Blood samples drawn at the end of rest and stress were assayed for ET-1 by ELISA (fmo/mL) and change from BL to AR calculated. As expected, the hemodynamic response to anger stress was significantly lower (p=0.015) among patients taking beta-blockers (n=81) than those not taking these agents (n=23). These two groups did not differ in ET-1 at BL (2.27±3.77 vs. 1.24±1.89, p = 0.98). Those not taking beta-blockers however, showed a significantly greater % increase in ET-1 from BL to AR (16.12%±29.09% vs. 2.14%±23.85%, p &lt;0.036); this relationship persisted after adjusting for rate pressure product, age, diabetes, HTN, and statin use (p=0.03). Comments: Beta-blocker use was associated with a significantly less anger-stress provoked increase in ET-1. This may be one of the mechanisms behind beneficial effects longitudinally of beta-blocker use on incident coronary events in patients with CAD.
Abstract 5076: Differential Response of Renal Tubule Sodium Transporters in Salt Sensitive and Salt Resistant Mouse Strains to Salt Load
Authors: Xiaoyan Wang, Ines Armando, Crisanto S Escano, Laureano Asico, Pedro A Jose
Journal: Circulation (2009)

We have reported that C57BL6 and SJL mice from Jackson laboratory have different responses to a chronic salt load: blood pressure increases in C57BL6 but not in SJL mice. We have suggested that the increase in blood pressure with NaCl loading in C57BL6 mice is due to a dysfunction of renal dopamine receptors caused by increased expression and activity of G protein-coupled receptor kinase 4. In order to determine if the salt sensitivity in C57BL6 mice can be related to increased expression of renal sodium transporters, we studied the effects of chronic NaCl loading on renal sodium transporters in these two mouse strains. C57BL6 and SJL mice (10 weeks old, male) were fed high NaCl (6%) or normal NaCl (0.8%NaCl) (n =5/group) diet. The blood pressures (measured by telemetry) were similar at baseline but increased in C57BL6 not in SJL mice after 1 and 3 weeks of salt loading. The urinary sodium excretions were also similar at baseline (2.34±0.27 vs 2.3±0.18,mEq/mg Cr, respectively) and increased to a lesser extent in C57BL6 than in SJL mice (1 wk: 4.39±0.9 vs 7.96±0.59, P&lt;0.05; 3 wks: 3.5±0.4 vs 5.0±0.9, P =0.16, respectively). On normal NaCl diet, the renal protein expression (immunoblotting) of sodium hydrogen exchanger 3 (NHE3, 287±33, % of SJL) sodium chloride cotransporter (NCC, 167±24, %) and β -epithelial sodium channel (ENaC,169±9, % ) was greater in C57BL6 than in SJL mice. Urinary aldosterone excretion and renal α -ENaC expression (an aldosterone-induced protein) were decreased by the salt load to a similar extent in the two mouse strains. In contrast, one and three weeks of salt loading decreased renal NCC, another aldosterone-induced protein, in SJL but not in C57BL6 mice. There was a difference in the molecular size of the NCC upper band (SJL = 160 kDa; C57BL6 = 175 kDa) while the 110 kDa band was similar in the two strains. The upper band is glycosylated NCC (proved by N-glycosidase F studies) which may be the active transporter; it remains to be determined if glycosylation affects NCC activity in mice. We conclude that the increased renal NCC expression, which is independent of aldosterone levels, may be responsible for the decreased sodium excretion in C57B6 mice. Our studies provide a renal molecular mechanism to the salt sensitivity in C57BL6 mice.
Abstract 5213: Correlations Between Reciprocal ST-segment Depression on the Baseline Electrocardiogram, Angiographic Findings and Clinical Outcomes in Patients With STEMI Treated With Primary PCI
Authors: Michael E Farkouh, Eugenia Nikolsky, James Reiffel, Ovidiu Dressler, David A Baran, Roxana Mehran, Alexandra J Lansky, Gregg W Stone
Journal: Circulation (2009)

Objective - To investigate correlations between reciprocal ST-segment depression on the baseline ECG, angiographic findings and clinical outcomes in patients with acute ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Methods - Among 3602 pts enrolled in the prospective, randomized Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 2401 pts had the baseline ECG analyzed by an independent ECG core lab as part of a formal substudy. Reciprocal ST-segment depression defined as &gt;0.1 mV depression in ≥1 adjacent leads in a territory remote from the site of ST-segment elevation was present in 1559 (64.9%) pts. Patients with posterior infarction were excluded. Angiographic analysis was performed by independent angiographic core lab. Results - Reciprocal ST-segment depression on baseline ECG correlated with higher incidence of non-LAD infarct vessel (72.2% vs. 37.9%), baseline TIMI flow grade 0/1 (67.6% vs. 57.3%), higher incidence of thrombus on baseline angiogram (84.3% vs. 75.2%), larger reference vessel diameter (median: 2.9 vs. 2.8 mm) and shorter time from symptoms onset to 1 st balloon inflation (median: 215.0 vs. 234.0 min) [all p&lt;0.0001] but not with incidence of multivessel disease (58.4% vs. 54.7%, p=0.08) or lower baseline LVEF (median: 60.2% vs. 59.6%, p=0.55). Clinical outcomes are presented in the Table . By multivariable analysis, baseline reciprocal ST-segment depression was not predictive of mortality at 30 days (hazard ratio [95%CI] = 1.00 [0.38, 2.66], p=0.99) or at 1 year (hazard ratio [95%CI] = 1.00 [0.47, 2.16], p=0.99). Conclusion - Reciprocal ST-segment depression on the presenting ECG does not predict an adverse prognosis in patients with STEMI treated by primary PCI and is not correlated with multivessel disease or more extensive myocardial damage as assessed by LVEF.
Abstract 5033: Safety and Efficacy of Carotid Stenting in the Very Elderly
Authors: Arthur Grant, Christopher White, Gary Ansel, Michael Bacharach, Christopher Metzger, Carlos Velez
Journal: Circulation (2009)

Background: Carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CEA) in patients at high-risk for complications from surgery. The very elderly (&gt; 79 years old) are one subgroup of patients identified as being at increased risk for carotid surgery. However, there is concern that the very elderly are also at increased risk for complications of CAS. A stroke and death rate of 12% was reported in very elderly patients during the roll-in phase of Carotid Revascularization Endarterectomy versus Stent Trial (CREST). We are reporting on a large clinical series of CAS with independent neurological assessment in the very elderly. Methods: Between 1994 and 2008, a consecutive series of 418 CAS patients (&gt; 79 years old) were treated at four high-volume centers with extensive CAS experience. Independent neurologic assessment was performed after CAS procedures. Thirty-day follow-up information was available in 389 patients. Results: The average age was 83.2±2.8 years. Most patients were male (63.2%) and the target lesion carotid stenosis was asymptomatic in two-thirds (68.2%) of patients. The majority of patients treated with CAS had a history of coronary artery disease (74.4%), hypertension (87.8%) and dyslipidemia (71.1%). One third (30.1%) were diabetic and more than half (56.5%) were current or former smokers. Embolic protection devices (EPD) were used in 78.7% of cases with the CAS procedure being performed prior to EPD availability being the most common reason for not using them. The 30-day incidence of stroke and death was 2.8% (11/389). The cumulative incidence of major cardiovascular events (stroke, death or myocardial infarction) during that time period was 3.3% (13/389). Conclusion: This large series of CAS with independent neurologic assessment is convincing evidence that the very elderly (&gt; 79 years old) can safely undergo CAS with stroke and death rates comparable to younger patients. The key to obtaining these excellent results is that CAS be performed by high-volume, experienced operators who exercise restraint regarding patient selection.