tbuckley/cabot-search huggingface dataset:
Abstract 4930: NADPH Oxidase 2 Regulates Stem/Progenitor Cell Mobilization via Modulating Hypoxic Gradient and Proteolytic Enzymes in Bone Marrow Following Hindlimb Ischemia
Authors: Norifumi Urao, Nihal Kaplan, Ronald McKinney, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2009)

Bone marrow (BM) microenvironment, which is regulated by hypoxia and proteolytic enzymes, is crucial for stem/progenitor cells mobilization during postnatal neovascularization. We demonstrated that NADPH oxidase2 (Nox2)-derived reactive oxygen species (ROS) in BM play a role in ischemia-induced stem/progenitor mobilization and revascularization. However, role of Nox2 in regulating BM microenvironment remains unknown. Here we show that hindlimb ischemia of mice increases Nox2 expression (2.2-fold) and ROS production (7.2-fold) in BM cells with peak at day 3, which is cotemporaneous with increase in circulating Sca-1 + /Flk-1 + endothelial progenitor cells (2.0-fold). These increases are inhibited in Nox2-deficient mice. Using hypoxia bioprobe, BM section shows that endosteum region is hypoxic in basal steady-state. After contralateral hindlimb ischemia, hypoxic areas are expanded with an increase in HIF-1alpha and Nox2 expression throughout the BM peaking at day 3 in wild type (WT) mice, which are markedly reduced in Nox2-deficient mice. In parallel, hindlimb ischemia increases the expansion of cKit + Lin − cells (1.6-fold) and angiogenic CXCR4 + VEGFR1 + Lin low progenitor cells (31%) in WT mice, which are inhibited in Nox2-deficient mice. This is due to increase in apoptotic (annexin V+) Lin- cells (2.0-fold) and decrease in proliferative (BrdU+) primitive stem/progenitor cKit + /Sca1 + /Lin − cells (36%). Moreover, hindlimb ischemia increases Akt phosphorylation (2.2-fold), MT1-MMP (4.2-fold) expression, and decreases its membrane-anchored inhibitor, RECK (62%) in BM, which are inhibited in Nox2-deficient mice. In summary, Nox2-derived ROS in BM regulate expansion of stem/progenitors, thereby promoting local hypoxia that increases HIF-1alpha in response to hindlimb ischemia. They also activate proteolytic enzyme activity in BM, which may facilitate mobilizing stem/progenitor cells leading to reparative neovascularization. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).
Abstract 4179: The Association of Sex Hormones with Arterial Compliance Differs Between Men and Women in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Dhananjay Vaidya, Sherita H Golden, Susan R Heckbert, Kiang Liu, Susan M Gapstur, Pamela Ouyang
Journal: Circulation (2006)

Studies show differences in vascular stiffness between older men and women. However, the relationship between sex hormones (SH) and vascular stiffness has not been studied. We examined the cross sectional association between endogenous SH (bioavailable testosterone, BioT; estradiol, E2; dehydroepiandrostenedione, DHEA; and sex-hormone binding globulin, SHBG) and carotid vascular compliance in men and women in MESA. Methods: We included 2966 men and 1886 postmenopausal women who were not on hormone therapy (45– 84 years, 35% white, 13% Chinese, 27% African-American, 24% Hispanic ethnicity). Baseline systolic and diastolic blood pressure (BP) were measured during carotid ultrasound examination. Carotid strain, a measure of distensibility (fractional change in carotid diameter) was measured from B-mode images. Because men and women differed in the relationship between strain and BP, analyses were performed separately by sex. Log-transformed carotid strain was regressed on log-transformed SH adjusting for log-transformed BP, age, race, glucose, smoking, and BMI. All SH were included in the same model. Differences of coefficients between men and women were evaluated by examining their standard errors. Results: Carotid strain was 6.8±2.7% in men and 7.0±3.2% in women (p=0.027). In regression analysis (Table ), in men, E2 was significantly associated with lesser carotid strain (increased stiffness) while the BioT was associated with borderline significance to higher strain. In women, there was no association between either E2 or T and carotid strain. DHEA and SHBG were not associated with compliance. No race interaction was found with these associations. Conclusion: E2 is associated with greater arterial stiffness in men, while BioT is weakly associated with lesser stiffness. Sex hormones are not associated with arterial stiffness in women. The hyperestro-genic hypoandrogenic state may impair vascular health in older men. Carotid Strain and Sex Hormones
Abstract 4185: Low Testosterone Level is an Independent Determinant of Endothelial Dysfunction in Men
Authors: Masahiro Akishita, Masayoshi Hashimoto, Yumiko Ohike, Katsuya Iijima, Masato Eto, Yasuyoshi Ouchi
Journal: Circulation (2006)

Background: Epidemiological studies have shown that relative hypogonadism is associated with the higher incidence of cardiovascular disease, the mechanism of which remains unknown. We investigated whether relative hypogonadism would be related to endothelial dysfunction in men. Methods: Consecutive 188 men (mean age ± SD = 47±15 years), who examined flow-mediated vasodilation (FMD) of the brachial artery using ultrasonography, were enrolled. The subjects with cardiovascular disease, malignancy, overt endocrine disease or having steroid hormones were excluded. Plasma hormone levels were determined after 12-hour fast in the morning, and the relationship between hormone levels and FMD was analyzed. Results: Total and free testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were significantly correlated with %FMD (r=0.262, 0.355 and 0.296, respectively; p&lt;0.001), while estradiol or cortisol was not. %FMD in the highest quartile of free testosterone was 1.7-fold higher than that in the lowest quartile (5.6±2.9 vs. 3.3±2.6 [mean±SD], p&lt;0.05). Multiple regression analysis revealed that total and free testosterone were related to %FMD independent of age, body mass index, hypertension, hypercholesterolemia, diabetes mellitus and smoking (β=0.197 and 0.240, respectively; p&lt;0.01), and independent of age, body mass index, systolic blood pressure, total cholesterol, HDL cholesterol, fasting plasma glucose, smoking and carotid intima-media thickness (β=0.211 and 0.259, respectively; p&lt;0.01). DHEA-S was not significantly related to %FMD on multivariate analysis. Conclusions: Low plasma testosterone level was associated with endothelial dysfunction in men independent of other risk factors, suggesting a protective effect of testosterone on the endothelium.
Abstract 4916: Hepatocyte Growth Factor Mediates Proangiogenic Effects by Activating the NADPH Oxidase Nox2
Authors: Katrin Schröder, Susanne Schütz, Sina Bätz, Katalin Wandzioch, Stephan Rennecke, Ralf P Brandes
Journal: Circulation (2009)

Hepatocyte growth factor (HGF) is a potent pro-angiogenic stimulus. We determined the effect of HGF on the mobilization of endothelial progenitor cells (EPCs) and endothelial aortic ring outgrowth as a model for ex vivo angiogenesis. As growth factor signaling frequently involves reactive oxygen species (ROS), we analyzed the effects of HGF on ROS formation and identified their enzymatic sources and the contribution of ROS to HGF signaling. In vivo application of HGF in mice induced the mobilization of EPCs (identified by FACS analysis as sca-1+, flk-1+, lineage negative mononuclear cells). Ex vivo, HGF stimulated endothelial cell outgrowth and increased the H2O2 formation of EPCs and the peroxynitrite formation in HUVEC as determined by peroxidase-catalyzed amplex red oxidation and DCHF-DA oxidation, respectively. This difference in ROS formation between EPCs and HUVECs was a consequence of the low expression of endothelial NO synthase (eNOS) in EPCs: In HUVECs, HGF increased the phosphorylation of eNOS at Ser1177, which increases the catalytic activity of the enzyme. As NADPH oxidases of the Nox family are important sources of ROS, their contribution to the signaling of HGF was determined. Down-regulation or genetic deletion of Nox2 prevented the HGF-stimulated ROS formation. As compared to wild type controls, the HGF-induced endothelial outgrowth was significantly reduced in aortic rings from Nox2 deficient (Nox2y/-) mice. Moreover, in vivo, the HGF-induced EPC mobilization was absent in Nox2y/- mice. Accordingly, HGF induced colony forming unit (CFU) formation in EPCs of WT but not Nox2y/- mice. ROS formation was essential for HGF-induced signaling: In HUVEC, HGF stimulated the phosphorylation of Jak2 and STAT3 and these effects were absent after depletion of the NADPH oxidase Nox2. We conclude that HGF-signaling critically involves the NADPH oxidase Nox2 and that ROS-formation by this enzyme contributes to the pro-angiogenic effects of HGF by stimulating EPC mobilization and endothelial activity.
Abstract 4927: Thrombin Activation of Proteinase-Activated Receptor 1 (PAR1) Induces Ca <sup>2+</sup> -Independent Vasoconstriction by Activating the Production of Reactive Oxygen Species in the Pulmonary Artery
Authors: Jun Maki, Mayumi Hirano, Katsuya Hirano
Journal: Circulation (2009)

Thrombotic pulmonary arteriopathy is associated with ~50% of primary pulmonary artery hypertension (PAH). Thrombin and its receptor PAR 1 are thus suggested to play a critical role in the pathogenesis and pathophysiology of PAH. However, the role of thrombin in the regulation of pulmonary artery contraction still remains largely unknown. This study thus aimed to elucidate the contractile mechanism of thrombin in the isolated porcine pulmonary artery. In the presence of extracellular Ca 2+ ([Ca 2+ ] o ), thrombin induced a sustained contraction with a small sustained elevation of [Ca 2+ ] i and an increase in myosin light chain (MLC) phosphorylation. The contractile effect of thrombin was abolished by either a protease inhibitor or a PAR 1 antagonist, while it was mimicked by an agonist peptide for PAR 1 , but not PAR 4 . In the absence of [Ca 2+ ] o , thrombin induced a sustained contraction to an extent similar to that seen in the presence of [Ca 2+ ] o , but no significant increase in [Ca 2+ ] i or MLC phosphorylation was observed. A similar Ca 2+ -independent contraction was induced by H 2 O 2 . Pretreatment with N -acetyl cysteine substantially inhibited the Ca 2+ -independent contraction induced by thrombin and H 2 O 2 . The fluorescence imaging of reactive oxygen species (ROS) revealed the thrombin- induced production of ROS in the absence of [Ca 2+ ] o . When a scavenger enzyme glutathione peroxidase was suppressed, the ROS production by thrombin was observed both in the presence and absence of [Ca 2+ ] o , thus suggesting that thrombin is capable of producing ROS regardless of the presence or absence of [Ca 2+ ] o , while this effect was veiled by the scavenger activity in the presence of [Ca 2+ ] o . Rho kinase inhibitor inhibited not only the thrombin-induced contraction in the presence of [Ca 2+ ] o , but also the Ca 2+ -independent contraction induced by thrombin and H 2 O 2 and the thrombin-induced ROS production, thus suggesting multiple roles of Rho kinase. This study thus provides the first evidence that the thrombin activation of PAR 1 induces pulmonary vasoconstriction via Ca 2+ -dependent as well as Ca 2+ -independent and ROS-mediated contractile mechanisms. PAR 1 is thus suggested to be useful as a novel therapeutic target for the treatment of PAH, especially when associated with thrombus.
Abstract 4172: Direct Effects of 5-methyl-tetrahydrofolate on Vascular Endothelium And Superoxide Production In Human Arteries And Veins
Authors: Charalambos Antoniades, Cheerag Shirodaria, Nicolas Warrick, Shijie Cai, Paul Leeson, David Taggart, Chandi Ratnatunga, Ravi Pillai, Keith Channon
Journal: Circulation (2006)

Background: 5-methyltetrahydrofolate (5MTHF), the circulating form of folic acid, reduces plasma homocysteine, but its direct effects on vascular function are unclear. We evaluated the direct effect of 5MTHF on endothelial function and superoxide (O 2 -) production in saphenous veins (SV) and internal mammary arteries (IMA) of patients undergoing CABG. Methods: Vasomotor responses to acetylcholine (ACh) were evaluated ex-vivo in vessel segments from 35 patients at baseline and after 45 minutes incubation with 5MTHF 0, 1, 10 and 100 μM. Vascular O 2 - was measured by lucigenin chemiluminescence in paired samples of SV and IMA after incubation with 5MTHF 0, 1 10 and 100 μM. The direct O 2 -scavenging capacity of 5MTHF was quantified using a xanthine/xanthine oxidase system, in comparison with vitamin C as positive control. Results. All the concentrations of 5MTHF similarly improved the vasomotor responses of SV to ACh (Fig a ). Whereas 5MTHF at high concentrations (100 μM) had direct O 2 - scavenging effect, no direct scavenging was observed with concentrations &lt;10μM (Fig b ). Vitamin C was a direct O 2 - scavenger even at 1μM (Fig b ). 5MTHF decreased O 2 - in both SV and IMA (Fig c ) compared to control, although there was no difference in O 2 - production between vessels exposed to 1, 10 and 100μΜ5MTHF. Conclusions. 5MTHF rapidly improves endothelial function and decreases O 2 - production in vessels from patients with CAD, by a mechanism other than the direct scavenging of O 2 - radicals. These data suggest that 5MTHF may have a direct effect on vascular function by modifying intracellular redox and improving NO bioavailability in human vessels.
Abstract 4184: Gender Difference in Utilization of Secondary Preventive Measures in Patients with CAD
Authors: Leslie Cho, Julie Huang, Danielle Brennan, Stanley L Hazen
Journal: Circulation (2006)

Background : Previous studies have suggested that women with cardiovascular disease may receive less aggressive care compared to men. Using a cardiology database from a tertiary referral center, we sought to determine if treatment difference still persist in the current era. Methods : 2462 patients who were referred for secondary prevention to Preventive Cardiology Clinic at The Cleveland Clinic between 1997 to 2004 were analyzed. The primary objective was to analyze utilization of effective secondary preventive therapies as stated by ACC/AHA guideline such as ASA, statin, B- blocker, or ACE inhibitor use between gender. Multivariate logistic regression analysis was performed to assess the independent effect of gender on all cause mortality. Results : Women were older (62.2 ± 11.1 vs. 59.4 ± 11.0, p&lt;0.001) and more likely to be hypertensive (68.1% vs. 56.1%, p&lt;0.001) than their male counterparts. However, they had similar rates of diabetes, smoking, and peripheral vascular disease. Overall, women were more likely to present with statistically higher baseline CRP (6.1 vs. 4.9 p&lt;0.001), LDL (135 vs. 116, p&lt;0.001), HDL (52 vs. 41, p&lt;0.001), total cholesterol (238 vs. 202, p&lt;0.001) than their male counterparts. Women were less likely to be on antiplatelet therapy (76.6 % vs. 85.0%, p&lt;0.001) and statins or any lipid lowering therapy (62.6% vs. 67.1%, p=0.04) compared to men on presentation. There was a trend toward higher all-cause mortality in women compared to men (21.5% vs. 17.8%, p=0.09) at 7 years. Conclusion : Even in the current era, women continue to receive less aggressive care compared to men. More efforts should be made to bridge the treatment gap between men and women.
Abstract 570: Catecholaminergic Polymorphic Ventricular Tachycardia - a Link between Mutation and Arrhythmia
Authors: Vivek Iyer, Roger J Hajjar, Antonis A Armoundas
Journal: Circulation (2006)

In this study, we investigate the mechanistic underpinnings of catecholaminergic polymorphic ventricular tachycardia (CPVT), a hereditary arrhythmia that leads to exercise- and stress-induced sudden cardiac death in young adults with structurally normal hearts. Recently, several mutations in cardiac calsequestrin (CSQN2) and the cardiac ryanodine receptor (RyR2) have been linked to CPVT. These mutant genes have been shown to affect RyR2 gating, however, the precise mechanisms by which they give rise to triggered activity remain uncertain. We modified a detailed mathematical model of the human left-ventricular subepicardial myocyte, using recently obtained experimental data, to study the aberrant calcium release events observed in mutant myocytes. First, CSQN2 mutations were modeled, by simulating disrupted luminal SR Ca 2+ sensing in the release process (the rate of release termination and rate of recovery from inactivation were increased). Second, a model for mutant RyR2 myocytes was formed by simulating the impaired coupled gating characteristic of reduced FKBP12.6 (calstabin) binding to the RyR2. Both models give rise to delayed afterdepolarizations (DADs) when paced in the presence of simulated isoproterenol. The mechanism for DADs in CSQN2 mutants appears to be secondary to premature recovery of receptors from a luminal calcium-dependent refractory state. In RyR2 mutants, DADs arise from receptors that activate with less synchrony, resulting in hyperactive, “leaky” receptors. Overall, these results provide plausible mechanisms by which defects in RyR2 gating may lead to the cellular triggers of arrhythmia, with implications for the development of targeted therapy.
Abstract 189: Simultaneous Imaging of the Single-Myocyte Optical Action Potentials and Intracellular Ca <sup>2+</sup> Dynamics in Langendorff-Perfused Rat Heart by a Novel Dual-Imaging Confocal Microscopy
Authors: Katsuji Fujiwara, Hideo Tanaka, Takuo Nakagami, Hiroki Mani, Takuji Tanabe, Masahito Oyamada, Tetsuro Takamatsu
Journal: Circulation (2006)

Rapid-scanning confocal imaging of intracellular Ca 2+ ([Ca 2+ ] i ) dynamics in the heart has revealed various abnormal [Ca 2+ ] i dynamics that indicate arrhythmogenic potential. For example, Ca 2+ waves under [Ca 2+ ] i overload and beat-to-beat alteration of Ca 2 + transients may lead to triggered arrhythmia and inhomogeneous excitation and conduction, respectively. However, it is unknown whether such abnormal [Ca 2+ ] i dynamics accompany altered electrical activities in the individual myocytes. To elucidate the link between [Ca 2+ ] i dynamics and the membrane potentials (V m ) of the myocytes in the heart we developed a novel dual-imaging system for both the [Ca 2+ ] i dynamics and optical V m at cellular levels. Optical signals for [Ca 2+ ] i and V m were obtained using in situ confocal microscopy (x40 objective lens, 2.2 ms/frame, 96x64 pixels) after loading the rat heart with fluo3/AM and RH237, respectively. The subepicardial myocardium of the heart was excited by Argon/Krypton (488/568nm) laser. The dual, non-overlapping signals for fluo3 and RH237, obtained by splitting the emitted light with a dichroic filter (565nm) and the respective emission filters of 535/40 nm and 774/50nm, were detected by a high-speed CCD camera (14 bits). Following results were obtained from 17 hearts. During sinus rhythm the myocytes exhibited spatially uniform Ca 2+ transients with simultaneous action potentials. Under perfusion with Ca 2+ -free solution Ca 2+ transients were diminished while the action potentials remained. The durations of these two parameters were stimulation-frequency dependent: the higher the frequency (up to 5Hz), the shorter the durations. At a stimulation frequency of 4Hz or higher Ca 2+ transients often showed beat-to-beat alternans while no discernible alternans was obtained in action potentials. Under [Ca 2+ ] i overload, cessation of high-frequency pacing at 5 Hz resulted in synchronous emergence of Ca 2+ waves among individual cells which accompanied fluctuations of the optical V m . In summary, we succeed in acquiring [Ca 2+ ] i dynamics V m and optical of individual myocytes simultaneously in the whole heart. This novel approach would provide important information to understand the mechanism of Ca 2+ -mediated arrhythmias.
Abstract 188: Abnormal Heart Rate Responses to Exercise and Susceptibility to Ventricular Fibrillation: Effect of Endurance Exercise Training
Authors: George E Billman, Monica Kukielka
Journal: Circulation (2006)

BACKGROUND : Both a large heart rate (HR) increase at exercise onset and a slow heart rate recovery following the termination of exercise have been linked to an increased susceptibility to ventricular fibrillation (VF). Endurance exercise training can enhance cardiac vagal and reduce cardiac sympathetic regulation and could, thereby, improve the exercise HR response and decrease the risk for VF. METHODS : To test this hypothesis, a 2-min coronary occlusion was made during the last min of an 18-min exercise test in dogs with healed myocardial infarctions: 20 had VF (S, susceptible) and 13 did not (R, resistant). On a previous day, HR and heart rate variability (HRV, 0.24 to 1.04 Hz frequency component; an index of cardiac vagal activity) responses to submaximal exercise were measured before and 30, 60 &amp; 120s after exercise onset and 30, 60 &amp; 120s following the termination of exercise. RESULTS : Larger HR increases and a slower HR recovery (ANOVA, both P&lt;0.01) were noted in the susceptible dogs (HR: 30s after exercise onset, S 179 ± 8.4 vs. R 156.8 ± 3.4 beats/min; 30s post exercise, S 186 ± 7.8 vs. R 164.2 ± 5.7 beats/min). These HR differences were accompanied by corresponding differences in cardiac vagal activity (HRV: 30s after exercise onset, S 4.0 ± 0.4 vs. R 4.8 ± 04 ln ms 2 ; 30s post exercise, S 2.4 ± 0.3 vs. R 3.8 3 0.4 ln ms 2 ). The dogs then received either a 10-wk exercise program (treadmill running; S n = 9; R n = 8) or an equivalent sedentary period (S n = 11; R n = 5). After 10-weeks, the response to exercise was not altered in the sedentary animals. In contrast, exercise training increased cardiac vagal activity such that HR at exercise onset was reduced while HR recovery increased. As a result, differences were no longer noted between the groups (30s after exercise onset: HR, S 151.4 ± 6.6 vs. R 149.5 ± 7.3 beats/min; HRV, S 5.8 ± 0.4 vs. R 5.6 ± 0.4 ln ms 2 ; 30s post exercise: HR, S 159.4 ± 7.7 vs. R 153.5 ± 5.3 beats/min; HRV, S 4.0 ± 0.6 vs. R 4.9 ± 0.5 ln ms 2 ). After training, the exercise plus ischemia tested provoked VF in sedentary but not trained susceptible dogs. CONCLUSION : Endurance exercise training can alter cardiac autonomic balance (increased cardiac vagal activity) to restore a more normal heart rate regulation and could, thereby, prevent ventricular fibrillation in high-risk individuals.