tbuckley/cabot-search huggingface dataset:
Abstract 5217: Endothelial Vasomotor Dysfunction in the Brachial Artery Predicts Development of Early Stage Renal Dysfunction in Patients With Type 2 Diabetes Mellitus
Authors: Mitsumasa Hirano, Takamitsu Nakamura, Yoshinobu Kitta, Isao Takishima, Yuri Ino, Tsuyoshi Kobayashi, Aritaka Makino, Keita Sano, Yukio Saito, Yasushi Kodama, Jun-ei Obata, Ken-ichi Kawabata, Kiyotaka Kugiyama
Journal: Circulation (2009)

Endothelial dysfunction in renal vasculature is implicated in the pathogenesis of renal failure in type 2 diabetes mellitus (DM). Endothelial dysfunction occurs in systemic vasculature of DM patients, and there may be a relationship between endothelial dysfunction in the brachial artery and renal vasculature. This study examined whether endothelial vasomotor dysfunction in the brachial artery predicts early renal dysfunction in DM patients. Methods: Flow-mediated endothelium-dependent dilation (FMD, % increase in artery diameter from baseline) in the brachial artery was measured in 275 consecutive DM patients with normal renal function at enrollment (serum creatinine levels [sCr] &lt;1.0 mg/dl, urinary albumin excretion [UAE] &lt; 25 mg/day and estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m 2 at baseline). They were prospectively followed for 1.5 years. The end point was development of early stage renal dysfunction, defined as occurrence of one or more of the following events: sCr ≥ 1.2 mg/dL, UAE ≥ 30 mg/day and eGFR &lt; 60 mL/min/1.73 m 2 . Results: During the follow-up period, early stage renal dysfunction developed in 63 (46.7%) patients with impaired FMD (&lt; 5.2%, 50 th percentile of the distribution) and in 17 (12.1 %) patients with the preserved FMD (≥ 5.2%) (p &lt; 0.0001). Using multivariate logistic analysis, the impaired FMD was an independent predictor of the development of early stage renal dysfunction (OR; 5.1, 95%CI; 2.62 - 9.68, p &lt; 0.0001) after adjustment with covariates, including hypertension, age, use of anti-diabetic drugs and CRP levels. Using a c -statistic, the predictive value of impaired FMD was significantly incremental over that of the conventional known risks including hypertension, age, use of anti-diabetic drug and CRP levels for progression of renal dysfunction (area under the ROC curve; 0.88 and 0.72, respectively, p = 0.01). Dilator response of the brachial artery to nitrates had no significant predictive value. Conclusions: Endothelial vasomotor dysfunction in the brachial artery is an independent predictor of development of early renal dysfunction in DM patients. The measurement of FMD is useful for identifying patients with type 2 DM at risk of developing future renal dysfunction.
Abstract 5196: LAR Deficiency Impairs Endothelial Barrier Function and Enhances Susceptibility to Atherosclerosis
Authors: Juxiang Li, Xi-Lin Niu, Marschall S Runge, Nageswara Madamanchi
Journal: Circulation (2009)

Vascular endothelium forms a selective semipermeable barrier that regulates vital physiological functions such as tissue-fluid hemostasis and host defense. Impairment of endothelial barrier function is an early step in vascular dysfunction, which ultimately leads to atherosclerosis. The endothelial adherens junction (AJ), a multi-protein complex consisting of VE-cadherin and its associated catenins: β -catenin, γ -catenin and p120-catenin, regulates endothelial barrier function. Protein tyrosine kinases and phosphatases (PTPs) regulate AJ integrity and vascular permeability by modulating protein tyrosine phosphorylation. To determine the role of leukocyte antigen-related (LAR) PTP in endothelial barrier function, we investigated whether LAR associates with and/or regulates tyrosine phosphorylation of AJ proteins and the paracellular pathway. LAR expression in human umbilical vein endothelial cells (HUVEC) and brain microvascular endothelial cells was localized to EC-EC boundaries. Knockdown of LAR impaired (by 129.8%), whereas overexpression enhanced (by 48%) barrier function in HUVEC, as measured by flux of 40 KDa FITC-Dextran through cell monolayers. Reciprocal co-immunoprecipitation and co-localization with double-label fluorescence microscopy demonstrated the interaction of LAR with VE-cadherin and β -catenin. When glutathione S-transferase-cLAR (cytosolic LAR) was incubated with HUVEC lysate or with purified recombinant cytosolic VE-cadherin, LAR directly bound to VE-cadherin. Glutathione S-transferase-cLAR also directly bound to β -catenin in HUVEC lysate. Overexpression of LAR decreased tyrosine phosphorylation of VE-cadherin and β -catenin in postconfluent HUVEC. Consistent with these findings, aortic endothelial permeability and bradykinin induced microvascular leakage in pial venules were increased in apoE−/−/LAR−/− mice compared with apoE−/− mice. Furthermore, apoE−/−/LAR−/− mice fed Western diet for 3 month had a significant increase in aortic atherosclerotic lesion formation compared with apoE−/− mice (p = 0.0198). Together these data indicate that LAR regulates endothelial barrier function and dysregulation of this phosphatase may result in vascular pathophysiology.
Abstract 4187: Glu27 β <sub>2</sub> -Adrenoceptor Polymorphism Enhances Body Weight Loss and 24h-Ambulatory Blood Pressure Reduction in Obese Women
Authors: Maria U Rondon, Claudio C Rezk, Ivani C Trombetta, Claudia L Forjaz, Marcia M Gowdak, Luciana T Batalha, Eliana Frazzatto, Alfredo Halpern, Sandra M Villares, Carlos E Negrao
Journal: Circulation (2006)

Introduction: Obesity has been linked to genetic and environmental determinants. Glu27 β 2 -adrenoceptor polymorphism has been associated with obesity and hypertension. In addition, muscle vasodilatation during physiological maneuvers is increased in individuals with Glu27 β 2 -adrenoceptor polymorphism. Not known is the impact of hypocaloric diet and exercise training on body weight and blood pressure (BP) in obese individuals with Glu27 β 2 -adrenoceptor polymorphism. Methods: From an initial sampling of 216 volunteers, we studied 42 middle-age normotensive obese women selected to represent two genotypes: 19 with Glu27 β 2 -adrenoceptor polymorphism and 23 wild type Gln27 (883± vs 86±2kg, P30.48, respectively). Hypocaloric diet consisted of a 600kcal/day reduction. Exercise training consisted of three 60-min exercise session/week during 4 months. Twenty-four hour ambulatory BP, cardiac output (CO, carbon dioxide rebreathing), and muscle sympathetic nerve activity (MSNA, microneurography) were evaluated pre and post interventions. Results: Hypocaloric diet and exercise training significantly decreased body weight, body mass index (BMI), 24-hour systolic BP, 24-hour pulse pressure, and CO in Glu27 and Gln27 groups. However, the comparisons between groups showed that the reduction in body weight (10.7±1 vs 7.4±1kg, P =0.02), BMI (4.1±0.4 vs 2.8±0.2kg/m 2 , P =0.01), 24-hour systolic BP (5.1±1 vs 2.2±1mmHg, P =0.05), 24-hour pulse pressure (3.6±1 vs 1.5±1mmHg, P =0.01), and CO (0.8±0.2 vs 0.4±0.1L/min, P =0.04) were significantly greater in Glu27 group than in Gln27group. No significant differences in diastolic BP, mean BP, and MSNA levels between groups were found. Conclusions: Obese women with Glu27 of the β 2 -adrenoceptor are more susceptible to body weight loss, and BP and CO reduction after hypocaloric diet and exercise training than wild type Gln27 obese women.
Abstract 5145: Central or Ambulatory Peripheral Blood Pressure: Which Best Relates to Target-organs and Future Mortality?
Authors: Chi-Ming Huang, Kang-Ling Wang, Hao-Min Cheng, Shao-Yuan Vhuang, Chih-Tai Ting, Edward G Lakatta, Frank Yin, Pesus Chou, Chen-Huan Chen
Journal: Circulation (2009)

Background: Central blood pressure (CBP) relates more to target organs and future cardiovascular mortality than peripheral blood pressure. It remains unknown whether single measurement of CBP is superior to multiple measurements of peripheral blood pressure from ambulatory blood pressure (AmBP) monitoring in the association with target organs and future mortality. Methods: CBP by carotid tonometry and 24-hour AmBP from a community-based population of 943 participants were analyzed. Cross-sectional association of the various blood pressure variables with left ventricular mass (LVM), carotid intima-media thickness (IMT), and estimated glomerular filtration rate (eGFR), and longitudinal association with all-cause and cardiovascular mortality over a 14.9-year median follow-up were investigated. Results: Among the 4 blood pressure variables, including the 24-hour SBP-Am and PP-Am, and SBP-C and PP-C, LVM correlated best with SBP-Am, whereas IMT and eGFR correlated best with PP-C. All 4 blood pressure variables, as well as target-organ indices predicted 14.9-year all-cause and cardiovascular mortality in the univariate analysis. With adjustment for conventional risk factors as well as LVM, IMT, and eGFR, individually entered SBP-Am, PP-Am, SBP-C or PP-C independently predicted cardiovascular mortality but not all-cause mortality. When the blood pressure variables were jointly entered into the multivariate models, only SBP-Am consistently predicted cardiovascular mortality. Conclusion: SBP-Am and PP-C relate differently to different target-organs. SBP-Am is more powerful than SBP-C or PP-C in the prediction of cardiovascular mortality.
Abstract 5215: Plaque Color in the Culprit Lesion is Associated With Incidence of Revascularization After Percutaneous Coronary Intervention for Acute Myocardial Infarction
Authors: Kazushi Saratani, Yoshitaka Iwanaga, Takahiro Hayashi, Shunichi Miyazaki
Journal: Circulation (2009)

Purpose : Plaque color is reported to have close relationship with the plaque vulnerability and the onset of acute coronary syndrome (ACS). However, few data are available on the relationship between plaque color and clinical outcome after the onset of acute myocardial infarction (AMI). Therefore, we evaluated the relationship of in vivo plaque color by coronary angioscopy (CAS) with the long-term clinical outcome including revascularization in patients after percutaneous coronary intervention (PCI) for AMI. Methods: Consecutive 230 patients with AMI were enrolled in the present study. The culprit lesions immediately before PCI were examined by CAS and were classified into three groups according to the color grade of the plaques: thick yellow plaque (TYP), yellow plaque (YP), or light yellow plaque (LYP). Results: There were no differences in lipid profile and other coronary risk factors among the three groups. However, during the follow-up of 2 years, the incidence of major adverse cardiac event (MACE) was significantly less in patients with TYP than those with YP or LYP by Kaplan-Meier analysis (P=0.006), which was driven primarily by a decreased incidence of revacularization (P=0.018). Furthermore, TYP was an independent predictor for long-term MACE after adjustment of predictive factors (age, Killip class, multivessel coronary artery disease, ejection fraction and body mass index). Conclusions: In AMI patients treated with PCI, the TYP in the culprit lesion independently predicted the long-term favorable prognosis, mainly due to less revascularization. This relationship might provide new insights for prevention of the secondary cardiac events after AMI.
Abstract 5106: C-c Chemokine Receptor 2 Inhibitor Ameliorates Diet-induced Insulin Resistance and Hepatic Steatosis in Mice
Authors: Yukinori Tamura, Toshinori Murayama, Manabu Minami, Yuki Nishikaze, Toru Kita, Masayuki Yokode, Hidenori Arai
Journal: Circulation (2009)

Visceral obesity and insulin resistance are common underlying factors of the metabolic syndrome (MetS), which is associated with a chronic low-grade inflammatory state and cardiovascular disease. C-C chemokine receptor-2 (CCR2), known as a receptor for MCP-1, plays a role in monocyte/macrophage (M φ ) recruitment and M φ -dependent inflammatory response. Recently, adipose tissue inflammation by M φ infiltration through MCP-1/CCR2 is considered to play a pivotal role in the development of visceral obesity and insulin resistance. However, the effect of postnatal inhibition of CCR2 on the development of diet-induced obesity (DIO) and insulin resistance remains unclear. To further explore the role of CCR2 in the development of visceral obesity and its associated metabolic disorders, we studied the effect of pharmacological inhibition of CCR2 before the onset of DIO in C57BL/6 mice. To study the effect of CCR2 inhibition, C57BL/6 mice were fed a high fat and high sugar diet with or without propagermanium (Pro, dose of 5mg and 50mg/kg/day), as a CCR2 inhibitor for 12 weeks from 6 weeks of age. At the end of study the gene expression of F4/80 and CD11c was reduced by 50%, while that of IL-10 and MGL-1 was increased by 2-fold in white adipose tissue (WAT), indicating that Pro suppressed adipose tissue M φ accumulation and shifted the infiltration of pro-inflammatory M1 M φ to anti-inflammatory M2 M φ . These data are consistent with a marked reduction of pro-inflammatory cytokine, TNF- α by Pro by 50% in WAT and liver. Diet-induced hypoadiponectinemia and hyperleptinemia were also improved by Pro treatment. Further, Pro treatment ameliorated insulin sensitivity and glucose tolerance, resulting in a marked reduction of plasma glucose and insulin level. Finally, Pro treatment decreased hepatic triglyceride contents by 45% in DIO mice. In conclusion, Pro improved obesity and its associated metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing infiltration of pro-inflammatory M1 M φ into WAT. Our data also implicate that CCR2 contributes to DIO and type 2 diabetes by accelerating adipose tissue inflammation, and that Pro may be a beneficial drug for the treatment of such metabolic disorders by blocking CCR2-mediated inflammation.
Abstract 5039: Globular and Full-length Adiponectin Induce NO-Dependent Vasodilation in Resistance Arteries of ZL but Not ZDF Rats
Authors: Peter M Schmid, Markus Resch, Christoph Birner, Benjamin Stoelcker, Gabriela Pietrzyk, Sabine Fredersdorf-Hahn, Christa Buechler, Günter A Riegger, Andreas Luchner, Dierk H Endemann
Journal: Circulation (2009)

Adiponectin increases NO-production in endothelial cell cultures and is reduced in the circulation of obese and diabetic patients, but it is not known whether adiponectin has a functional effect on small resistance arteries. In order to address this question, we assessed the direct vasodilatory response of mesenteric resistance arteries of Zucker diabetic fatty (ZDF) rat and the Zucker lean (ZL) rats to globular (gAd) and full-length adiponectin (fAd) in a small vessel myograph after precontraction with norepinephrine. Serum adiponectin levels measured by ELISA were significantly higher in ZL than in ZDF rats (ZL 4.0±0.1 μ g/l vs ZDF 2.9±0.2 μ g/l; p&lt;0.001). Both gAd and fAd induced a relevant dose dependent vasodilation in ZL, but not ZDF rats (max. vasodilation to gAd: ZL 21.0±0.9% vs ZDF 2.9±0.9%; p&lt;0.001. max. vasodilation to fAd: ZL 23.8±1.2% vs ZDF 1.4±1.1%; p&lt;0.001). This vasodilatory effect in ZL rats could totally be blunted by preincubation with L-NAME (p&lt;0.001) indicating that it is exclusively mediated by NO. ZDF rats showed a significantly lower endothelium-dependent vasodilation response to acetylcholine (max. vasodilation: ZL 96.7±5.5% vs ZDF 60.1±6.0%; p&lt;0.001). The additional administration of low dose gAd or fAd could not improve the vasodilatory response to ACh. The gene expressions of AdipoR1 and AdipoR2 quantified by real-time RT-PCR were not significantly different in both animal models, AdipoR2 only tended to be higher expressed in ZDF rats (ZL 0.62±0.03 vs ZDF 0.68±0.06; p=0.061). But AdipoR1 was significantly more abundant expressed than AdipoR2 in resistance arteries of both ZL and ZDF rats (ZL: 1.06±0.04 vs 0.62±0.03; p&lt;0.001. ZDF: 1.06±0.08 vs 0.68±0.06; p&lt;0.001). In conclusion, we showed that adiponectin exerts a relevant NO-mediated vasodilation in resistance arteries of normal control rats. Reduced adiponectin serum levels and a blunted response to adiponectin in diabetic animals may contribute to endothelial dysfunction and thus play a role in the pathogenesis of atherosclerosis. In diabetes mellitus, adiponectin receptors are not downregulated in resistance arteries indicating a dysfunction downstream of the receptors.
Abstract 4923: Prostacyclin Analogues Activates Calcium-dependent Potassium (K <sub>Ca</sub> ) Channels via PPAR <i>β</i> / <i>δ</i> in Pulmonary Artery
Authors: Yingji Li, Michelle Connolly, Bi Tang, Chandran Nagaraj, Zoltán Bálint, Freya Smolle-Jüttner, Helmut Popper, Andrea Olschewski
Journal: Circulation (2009)

Pulmonary hypertension is associated with vasoconstriction, thrombosis and proliferation, and the lack of endogenous prostacyclin. Prostacyclin and its analogues are potent vasodilators, representing an important pillar of modern therapy of this devastating disease. Potassium channels determine the membrane potential of pulmonary artery smooth muscle cells (PASMCs) and are important controllers of their calcium homeostasis and consequently the pulmonary arterial tone. In the present study, we investigated the signaling pathway and effects of the stable prostacyclin analogues treprostinil and iloprost in primary human PASMCs and isolated rat pulmonary artery. We employed the whole-cell patch-clamp technique combined with small interfering (si)RNA and live-cell calcium imaging on human PASMCs and the myograph-mounted isolated intrapulmonary artery model. We found that treprostnil (10 nM) and iloprost (10 nM) hyperpolarized primary human PASMCs (13.1 ± 2.2 mV, p &lt; 0.01 and 15.7 ± 2 mV, p &lt; 0.01 respectively, n = 6 for each group) and activated K Ca (IC 50 = 0.2 ± 0.05 nM and IC 50 = 0.5 ± 0.2 nM respectively, n = 5 for each group) at clinically relevant concentrations. The IP receptor antagonist RO1138452 (10 μ M) and PKA blocker KT5720 (1 mM) abolished these effects. In the siRNA-transfected cells no enhancement of K Ca current was detected. The novel PPAR β / δ antagonist GSK0660 (10 nM), abolished the activation of K Ca current by iloprost or treprostinil, whereas the selective PPAR β / δ agonist GW0742 (10 nM) activated the K Ca current. Calcium imaging measurements supported these data showing that GW0742 reduced the basal intracellular calcium concentration by 9.41±2.99 % (n = 25, p &lt; 0.01) compared to the baseline in human PASMCs. Consequently, GW0742 caused relaxation in U46619 -preconstricted rat intrapulmonary arteries (IC 50 = 9.42 μ M, n = 5). This is the first study implicating K Ca in the prostacyclin analogue- mediated hyperpolarization via PPAR β / δ in human PASMCs. This might represent a novel pathway related to the vasodilating effects of prostanoids.
Abstract 4852: High Resting Velocity in Intramyocardial Coronary Artery is Related to Elevated Plasma Brain Natriuretic Peptide Levels in Patients With Hypertension
Authors: Yasuji Doi, Ken-ichiro Okada, Shoji Kaibe, Noritoshi Ito, Tohru Hayashi
Journal: Circulation (2009)

Narrowings in intramyocardial coronary arteries (IMCA) and elevated plasma brain natriuretic peptide (BNP) levels have been demonstrated in hypertensive heart disease. To clarify the relation between abnormalities in IMCA and plasma BNP levels, 228 consecutive patients with hypertension were studied using high-frequency transthoracic Doppler echocardiography. We defined IMCA flow as abnormal one if acceleration flow in IMCA, indicating the presence of vessel narrowing, was detected by color flow mapping and the pulsed Doppler study demonstrated higher peak diastolic flow velocity than 32cm/sec (i.e. normal value + 2SD) in the site. Such abnormal flow in IMCA was demonstrated in 59 (56%) of 102 hypertensive patients with left ventricular hypertrophy (LVH) and in 36 (24%) of the other 126 hypertensive patients without LVH. Independent of LVH, the 95 hypertensive patients with abnormal IMCA flow had higher peak diastolic velocities in the IMCA (47.9±16.5 cm/s vs. 24.3±5.4 cm/s, p&lt;0.01) and more elevated plasma BNP levels (131.0±24.4 pg/ml vs. 45.8±5.7 pg/ml, p&lt;0.01) than those without abnormal IMCA flow. Furthermore, peak diastolic velocities had a significant correlation with log BNP values (p&lt;0.01). The index of % area stenosis (IAS) estimated by the continuity equation was 46±14% at the site of acceleration flow, indicating the presence of mild to moderate lumen narrowing in the IMCA. The patients with the IAS of 50% and over had significantly higher log BNP values as compared to those with the IAS of less than 50% (p&lt;0.05), indicating plasma BNP levels may be elevated by factors associated with lumen narrowing in the IMCA. Conclusions: High resting velocity in IMCA is at least partly related to elevated BNP levels in patients with hypertension independent of LVH.
Abstract 5144: The Obligatory Role of Heat Shock Protein 90 in iNOS Induction in Postischemic Hearts
Authors: Suxin Luo, Tingting Wang, Lucy L Chen, Yong Xia
Journal: Circulation (2009)

Inducible nitric oxide synthase (iNOS) plays important roles in the process of myocardial infarction, heart failure, and cardiac preconditioning. The expression of iNOS is mainly induced by inflammatory substances such as endotoxins and cytokines. NF- κ B and STAT-1 are the two transcriptional factors that mediate iNOS expression in stimulated cells. Previous studies showed that heat shock protein 90 (Hsp90) associates with iNOS and this association enhances iNOS activity. Here we show that Hsp90 is also essential for iNOS induction. To determine the role of Hsp90 in iNOS induction, we treated mouse macrophages (RAW 264.7) with lipopolysaccharide (LPS, 1 μ g/ml) and interferon- γ (IFN- γ , 100 units/ml) in the absence and presence of Hsp90 inhibitor geldanamycin (1 μ M). Hsp90 inhibition completely prevented iNOS protein expression. RT-PCR experiments showed that iNOS mRNA transcription was blocked by Hsp90 inhibition. Radicicol (10 μ M), another Hsp90 inhibitor whose structure is different from that of geldanamycin, also blocked iNOS mRNA transcription. Further experiments showed that Hsp90 inhibition prevented NF- κ B activation in LPS-treated cells. In IFN- γ -stimulated cells, STAT-1 activation was also abolished by Hsp90 inhibition. To explore whether these findings from cultured cells occurred in diseases, we performed in vivo myocardium infarction on mice. While no iNOS expression was detected in the heart of mice in sham group, iNOS mRNA and proteins were observed in the infarcted areas of the hearts subjected to 1-hr coronary artery (LAD) occlusion and 24-hr reperfusion. Geldanamycin (4 mg/kg, i.p.) completely prevented iNOS mRNA and protein expression in the infarcted myocardium ( P &lt;0.001, n=5). Taken together, these results demonstrate that besides acting as an allosteric enhancer, Hsp90 is also required for iNOS gene transactivation. Intervening Hsp90 may represent a novel approach to modulate iNOS expression in myocardial infarction and cardiac preconditioning.