bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feeding blueberry diets inhibits angiotensin II-converting enzyme (ACE) activity in spontaneously hypertensive stroke-prone rats
Authors: Wiseman Waylon , Egan Jennifer M. , Slemmer Jennifer E. , Shaughnessy Kevin S. , Ballem Katherine , Gottschall-Pass Katherine T. , Sweeney Marva I. 
Published: December 2010

Feeding flavonoid-rich blueberries to spontaneously hypertensive stroke-prone rats (SHRSP) lowers blood pressure. To determine whether this is due to inhibition of angiotensin-converting enzyme (ACE) activity, as seen with other flavanoid-rich foods, we fed blueberries to SHRSP and normotensive rats and analyzed ACE activity in blood and tissues. After 2 weeks on a control diet, the hypertensive rats showed 56% higher levels of ACE activity in blood as compared with the normotensive rats (p < 0.05). Feeding a 3% blueberry diet for 2 weeks lowered ACE activity in the SHRSP (p < 0.05) but not the normotensive rats. ACE activity in plasma of SHRSP was no longer elevated at weeks 4 and 6, but blueberry feeding inhibited ACE in SHRSP after 6 weeks. Blueberry diets had no effect on ACE activity in lung, testis, kidney, or aorta. Our results suggest that dietary blueberries may be effective in managing early stages of hypertension, partially due to an inhibition of soluble ACE activity.
The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury
Authors: Khaksari Mohammad , Soltani Zahra , Shahrokhi Nader , Moshtaghi Gholamreza , Asadikaram Gholamreza 
Published: December 2010

Cytokines play an important role in the pathophysiology of traumatic brain injury (TBI). This study was designed to determine the effects of administering progesterone (P) and estrogen (E), alone and in combination, on brain water content, blood–brain barrier (BBB) disturbance, and brain level of cytokines following diffuse TBI. Ovariectomized rats were divided into 9 groups, treated with vehicle, E1, E2, P1, P2, E1+P1, E1+P2, E2+P1, and E2+P2. Levels of BBB disruption (5 h), cytokines, and water content (24 h) were evaluated after TBI induced by the Marmarou method. Physiological (E1 and P1) and pharmacological (E2 and P2) doses of estrogen and progesterone were administered 30 min after TBI. Water content in the E1+P2-treated group was higher than in the E1-treated group. The inhibitory effect of E2 on water content was reduced by adding progesterone. The inhibitory effect of E1 and E2 on Evans blue content was reduced by treatment with E1+P1 and E2+P2, respectively. The brain level of IL-1β was reduced in E1 and E2, after TBI. In the E2+P2-treated group, this level was higher than in the E2-treated group. The brain level of TGF-β was also elevated by the administration of progesterone and estrogen alone, and reduced when the hormones were administered in combination. In conclusion, a combined administration of progesterone and estrogen inhibited the decreasing effects of administration of progesterone and estrogen alone on water content and BBB disruption that mediated to change the proinflammatory cytokines.
Role of large-conductance Ca2+-activated K+ channels in adenosine A1 receptor-mediated pharmacological postconditioning in H9c2 cells
Authors: Fretwell Laurice , Dickenson John M. 
Published: December 2010

Ischaemic postconditioning is a phenomenon whereby short periods of ischaemia applied during the start of reperfusion protect the myocardium from the damaging consequences of reperfusion. As such, pharmacological-induced postconditioning represents an attractive therapeutic strategy for reducing reperfusion injury during cardiac surgery and following myocardial infarction. The primary aim of this study was to determine the role of large-conductance Ca2+-activated potassium channels (BKCa channels) in adenosine A1 receptor-induced pharmacological postconditioning in the rat embryonic cardiomyoblast-derived cell line H9c2. H9c2 cells were exposed to 6 h hypoxia (0.5% O2) followed by 18 h reoxygenation (H/R) after which cell viability was assessed by monitoring lactate dehydrogenase (LDH) release and caspase-3 activation. The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA; 100 nmol/L) or the BKCa channel opener NS1619 (10 µmol/L) were added for 30 min at the start of reoxygenation following 6 h hypoxic exposure. Where appropriate, cells were treated (15 min) before pharmacological postconditioning with the BKCa channel blockers paxilline (1 µmol/L) or iberiotoxin (100 nmol/L). Pharmacological postconditioning with CPA or NS1619 significantly reduced H/R-induced LDH release. Treatment with paxilline or iberiotoxin attenuated adenosine A1 receptor and NS1619-induced pharmacological postconditioning. These results have shown for the first time that BKCa channels are involved in adenosine A1 receptor-induced pharmacological postconditioning in a cell model system.
Long-term swimming exercise does not modulate the Akt-dependent endothelial nitric oxide synthase phosphorylation in healthy mice
Authors: Pellegrin Maxime , Miguet-Alfonsi Carole , Berthelot Alain , Mazzolai Lucia , Laurant Pascal 
Published: December 2010

Molecular mechanisms by which exercise exerts cardiovascular benefits are poorly understood. Exercise-induced increase of endothelial NO synthase (eNOS) phosphorylation through the protein kinase Akt has been shown to be a key mechanism underlying the beneficial effect of exercise in coronary artery disease patients. We examined whether this protective pathway might also be activated in long-term-exercised healthy mice. C57BL/6 wild-type mice swam for 24 weeks. A group of sedentary animals were used as controls. Aortic levels of total protein kinase Akt (protein kinase B), phosphorylated Akt at ser473 (p-Akt), total eNOS, phosphorylated eNOS at Ser1177 (p-eNOS), and PECAM-1 (platelet endothelial cell adhesion molecule-1) were assessed by Western blotting. Protein expressions of Akt, p-Akt, eNOS, p-eNOS, and PECAM-1 were not modulated by 24 weeks of exercise. The Akt-dependent eNOS phosphorylation did not seem to be a primary molecular adaptation in response to long-term exercise in healthy mice.
Serum Hepcidin and Macrophage Iron Correlate With MCP-1 Release and Vascular Damage in Patients With Metabolic Syndrome Alterations
Authors: Valenti Luca , Dongiovanni Paola , Motta Benedetta Maria , Swinkels Dorine W. , Bonara Paola , Rametta Raffaela , Burdick Larry , Frugoni Cecelia , Fracanzani Anna Ludovica , Fargion Silvia 
Published: December 2010

Objective—
Increased body iron stores and hepcidin have been hypothesized to promote atherosclerosis by inducing macrophage iron accumulation and release of cytokines, but direct demonstration in human cells is lacking. The aim of this study was to evaluate the effect of iron on cytokine release in monocytes ex vivo and the correlation with vascular damage and to evaluate the relationship among serum levels of hepcidin, cytokines, and vascular damage in patients with metabolic syndrome alterations.

Methods and Results—

Manipulation of iron status with ferric ammonium citrate and hepcidin-25 induced monocyte chemoattractant protein (MCP)-1 and interleukin-6 in human differentiating monocytes of patients with hyperferritinemia associated with the metabolic syndrome (n=11), but not in subjects with hemochromatosis or
HFE
mutations impairing iron accumulation (n=15), and the degree of induction correlated with the presence of carotid plaques, detected by echocolor–Doppler. In monocytes of healthy subjects (n=7), iron and hepcidin increased the mRNA levels and release of MCP-1, but not of interleukin-6. In 130 patients with metabolic alterations, MCP-1 levels, as detected by ELISA, were correlated with hepcidin-25 measured by time-of-flight mass spectrometry (
P
=0.005) and were an independent predictor of the presence of carotid plaques (
P
=0.05).

Conclusion—
Hepcidin and macrophage iron correlate with MCP-1 release and vascular damage in high-risk individuals with metabolic alterations.
Platelet-Endothelial Cell Adhesion Molecule-1 Regulates Endothelial NO Synthase Activity and Localization Through Signal Transducers and Activators of Transcription 3–Dependent NOSTRIN Expression
Authors: McCormick Margaret E. , Goel Reema , Fulton David , Oess Stefanie , Newman Debra , Tzima Ellie 
Published: December 2010

Background—
NO produced by the endothelial NO synthase (eNOS) is an important regulator of cardiovascular physiological and pathological features. eNOS is activated by numerous stimuli, and its activity is tightly regulated. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in regulating eNOS activity in response to shear stress. The current study was conducted to determine the role of PECAM-1 in the regulation of basal eNOS activity.

Methods and Results—
We demonstrate that PECAM-1–knockout ECs have increased basal eNOS activity and NO production. Mechanistically, increased eNOS activity is associated with a decrease in the inhibitory interaction of eNOS with caveolin-1, impaired subcellular localization of eNOS, and decreased eNOS traffic inducer (NOSTRIN) expression in the absence of PECAM-1. Furthermore, we demonstrate that activation of blunted signal transducers and activators of transcription 3 (STAT3) in the absence of PECAM-1 results in decreased NOSTRIN expression via direct binding of the signal transducers and activators of transcription 3 to the NOSTRIN promoter.

Conclusion—
Our results reveal an elegant mechanism of eNOS regulation by PECAM-1 through signal transducers and activators of transcription 3–mediated transcriptional control of NOSTRIN.
Systemic Markers of Interferon-γ–Mediated Immune Activation and Long-Term Prognosis in Patients With Stable Coronary Artery Disease
Authors: Pedersen Eva Ringdal , Midttun Øivind , Ueland Per Magne , Schartum-Hansen Hall , Seifert Reinhard , Igland Jannicke , Nordrehaug Jan Erik , Ebbing Marta , Svingen Gard , Bleie Øyvind , Berge Rolf , Nygård Ottar 
Published: December 2010

Objective—
Interferon γ (IFN-γ) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-γ stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kyunernine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease.

Methods and Results—
Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR).

Conclusion—
In patients with stable angina pectoris, systemic markers of IFN-γ activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-γ to acute atherosclerotic complications.
Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia
Authors: Morishita Ryuichi , Makino Hirofumi , Aoki Motokuni , Hashiya Naotaka , Yamasaki Keita , Azuma Junya , Taniyama Yoshiaki , Sawa Yoshiki , Kaneda Yasufumi , Ogihara Toshio 
Published: December 2010

Objective—
To evaluate the safety and feasibility of intramuscular gene transfer using naked plasmid DNA-encoding hepatocyte growth factor (HGF) and to assess its potential therapeutic benefit in patients with critical limb ischemia.

Methods and Results—

Gene transfer was performed in 22 patients with critical limb ischemia by intramuscular injection of HGF plasmid, either 2 or 4 mg, 2 times. Safety, ankle-brachial index, resting pain on a 10-cm visual analog scale, wound healing, and walking distance were evaluated before treatment and at 2 months after injection. No serious adverse event caused by gene transfer was detected over a follow-up of 6 months. Of particular importance, no peripheral edema, in contrast to that seen after treatment with vascular endothelial growth factor, was observed. In addition, the systemic HGF protein level did not increase during the study. At 2 months after gene transfer, the mean±SD ankle-brachial index increased from 0.46±0.08 to 0.59±0.13 (
P
<0.001), the mean±SD size of the largest ischemic ulcers decreased from 3.08±1.54 to 2.32±1.88 cm (
P
=0.007), and the mean±SD visual analog scale score decreased from 5.92±1.67 to 3.04±2.50 cm (
P
=0.001). An increase in ankle-brachial index by >0.1, a reduction in ulcer size by >25%, and a reduction in visual analog scale score by >2 cm at 2 months after gene transfer were observed in 11 (64.7%) of 17 limbs, 18 (72%) of 25 ulcers, and 8 (61.5%) of 13 limbs, respectively.

Conclusion—
Intramuscular injection of naked HGF plasmid is safe and feasible and can achieve successful improvement of ischemic limbs as sole therapy.
Transcriptional Activation of Apolipoprotein CIII Expression by Glucose May Contribute to Diabetic Dyslipidemia
Authors: Caron Sandrine , Verrijken An , Mertens Ilse , Samanez Carolina Huaman , Mautino Gisèle , Haas Joel T. , Duran-Sandoval Daniel , Prawitt Janne , Francque Sven , Vallez Emmanuelle , Muhr-Tailleux Anne , Berard Isabelle , Kuipers Folkert , Kuivenhoven Jan A. , Biddinger Sudha B. , Taskinen Marja-Riitta , Van Gaal Luc , Staels Bart 
Published: December 2010

Objective—
Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism.

Methods and Results—

Liver-specific insulin receptor–deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces
apoCIII
transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element–binding protein and hepatocyte nuclear factor-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin.

Conclusion—

Glucose induces
apoCIII
transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.
Anatomical and Technical Factors Associated With Stroke or Death During Carotid Angioplasty and Stenting
Authors: Naggara Olivier , Touzé Emmanuel , Beyssen Bernard , Trinquart Ludovic , Chatellier Gilles , Meder Jean-François , Mas Jean-Louis 
Published: December 2010

Background and Purpose—
The purposes of this study were to assess the relationships between anatomic and technical factors and the 30-day risk of stroke or death after carotid angioplasty and stenting in the Endarterectomy versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial and to perform a systematic review of the literature.

Methods—
We included patients from EVA-3S in whom carotid stenting was attempted irrespective of allocated treatment. Two radiologists blinded to clinical data independently assessed the aortic arch and carotid arteries on procedural angiograms. In addition, we performed a systematic review of studies that reported 30-day risk of stroke or death in relation with arterial anatomy and technique. Outcomes were stroke or death and stroke occurring within 30 days of the carotid angioplasty and stenting procedure.

Results—
Two hundred sixty-two patients from EVA-3S fulfilled the inclusion criteria (including 1 initially allocated to surgery and 13 in whom stent insertion failed).Within 30 days after the procedure, 25 (9.5%) patients had a stroke or had died. The risk of stroke or death was higher in patients with internal carotid artery–common carotid artery angulation ≥60° (relative risk, 4.96; 2.29 to 10.74) and lower in those treated with cerebral protection devices (relative risk [RR], 0.38; 0.17 to 0.85). In the systematic review (56 studies; 34 398 patients), the risk of stroke or death was higher in patients with left-sided carotid angioplasty and stenting (RR, 1.29; 1.05 to 1.58), increased internal carotid artery–common carotid artery angulation (RR, 3.41; 1.52 to 7.63), and when the target internal carotid artery stenosis was >10 mm (RR, 2.36; 1.28 to 3.38). There was no significant increase in risk of stroke or death in patients with Type III aortic arch, aortic arch calcification, or with ostial involvement, calcification, ulceration or degree of stenosis of the target internal carotid artery stenosis. The use of a cerebral protection device was associated with a lower risk of stroke or death (RR, 0.55; 0.41 to 0.73). Risk was not related with stent or cerebral protection device type.

Conclusions—
Our results strongly suggest that some technical and anatomic factors, especially extreme angulation of the carotid artery, have an impact on the risks of carotid angioplasty and stenting.
Remote Limb Ischemic Postconditioning Protects Against Neonatal Hypoxic–Ischemic Brain Injury in Rat Pups by the Opioid Receptor/Akt Pathway
Authors: Zhou Yilin , Fathali Nancy , Lekic Tim , Ostrowski Robert P. , Chen Chunhua , Martin Robert D. , Tang Jiping , Zhang John H. 
Published: December 2010

Background and Purpose—
Remote ischemic postconditoning, a phenomenon in which brief ischemic stimuli of 1 organ protect another organ against an ischemic insult, has been demonstrated to protect the myocardium and adult brain in animal models. However, mediators of the protection and underlying mechanisms remain to be elucidated. In the present study, we tested the hypothesis that remote limb ischemic postconditioning applied immediately after hypoxia provides neuroprotection in a rat model of neonatal hypoxia–ischemia (HI) by mechanisms involving activation of the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.

Methods—
HI was induced in postnatal Day 10 rat pups by unilateral carotid ligation and 2 hours of hypoxia. Limb ischemic postconditioning was induced by 4 conditioning cycles of 10 minutes of ischemia and reperfusion on both hind limbs immediately after HI. The opioid antagonist naloxone, phosphatidylinositol-3-kinase inhibitor wortmannin, or opioid agonist morphine was administered to determine underlying mechanisms. Infarct volume, brain atrophy, and neurological outcomes after HI were evaluated. Expression of phosphorylated Akt, Bax, and phosphorylated ERK1/2 was determined by Western blotting.

Results—
Limb ischemic postconditioning significantly reduced infarct volume at 48 hours and improved functional outcomes at 4 weeks after HI. Naloxone and wortmannin abrogated the postconditioning-mediated infarct-limiting effect. Morphine given immediately after hypoxia also decreased infarct volume. Furthermore, limb ischemic postconditioning recovered Akt activity and decreased Bax expression, whereas no differences in phosphorylated ERK1/2expression were observed.

Conclusions—
Limb ischemic postconditioning protects against neonatal HI brain injury in rats by activating the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.
Pharmacogenetic Effect of the Stromelysin (MMP3) Polymorphism on Stroke Risk in Relation to Antihypertensive Treatment
Authors: Sherva Richard , Ford Charles E. , Eckfeldt John H. , Davis Barry R. , Boerwinkle Eric , Arnett Donna K. 
Published: December 2010

Background and Purpose—
Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the Genetics of Hypertension Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine whether it modifies clinical outcome response to blood pressure–lowering drugs.

Methods—
The effect of the MMP3 5A/6A polymorphism on stroke rates was examined by using multivariate-adjusted Cox regression models, including a test for interactions between genotype and antihypertensive drug class.

Results—

Compared with participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard ratio=1.32; 95% CI, 1.08 to 1.61;
P
=0.007) and 5A/6A individuals taking lisinopril had lower stroke rates (hazard ratio
interaction
=0.74; 95% CI, 0.53 to 1.04;
P
interaction
=0.08), whereas 5A/5A individuals taking lisinopril had the lowest stroke rate (hazard ratio
interaction
=0.51; 95% CI, 0.31 to 0.85;
P
interaction
=0.009). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin vs chlorthalidone.

Conclusions—
The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared with patients treated with chlorthalidone, whereas a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00563901.
Increased Risk of Stroke in the Year After a Hip Fracture
Authors: Kang Jiunn-Horng , Chung Shiu-Dong , Xirasagar Sudha , Jaw Fu-Shan , Lin Herng-Ching 
Published: December 2010

Background and Purpose—
Stroke is a documented risk factor for hip fracture. However, no documented studies are available on the risk of stroke among patients with hip fracture. This study investigated the frequency and risk of stroke after hip fracture using a nationwide population-based study.

Methods—
The study cohort included 2101 patients hospitalized with a principal diagnosis of hip fracture from 2001 to 2004. The comparison cohort consisted of 6303 randomly selected subjects matched on sex, age, and year of index healthcare use as controls. We tracked patients for a 1-year period from their index healthcare encounter to identify those who had a stroke. Stratified Cox proportional hazard regression was performed to evaluate the association of hip fracture with subsequent stroke during 1-year follow-up.

Results—

Of a total of 8404 patients, 86 (4.1%) from the study group and 170 (2.7%) from the comparison group had strokes during the follow-up period (
P
<0.001). The stratified Cox proportional analysis shows that the 1-year crude hazard of stroke among patients with hip fracture was 1.55 times (95% CI, 1.19 to 2.03;
P
=0.001) that of the comparison group. Furthermore, after adjusting for the major cardiovascular risk factors, the increased stroke risk of patients with hip fracture persisted at about the same level as in the unadjusted analysis (hazard ratio, 1.53; 95% CI, 1.17 to 2.01;
P
=0.002).

Conclusion—
Hip fracture is associated with increased risk of stroke in the next year.