bluuebunny/crossref_metadata_2025 huggingface dataset:
Sildenafil decreased cardiac cell apoptosis in diabetic mice: reduction of oxidative stress as a possible mechanism
Authors: Ebrahimi Farzad , Shafaroodi Hamed , Asadi Shahrzad , Nezami Behtash Ghazi , Ghasemi Mehdi , Rahimpour Sina , Hashemi Mehrdad , Doostar Yousef , Dehpour Ahmad Reza
Published: September 2009

Oxidative stress plays a dominant role in the pathogenesis of cardiac cell apoptosis in diabetic patients. Sildenafil has been demonstrated to have antioxidant effects. In this study, the effects of sildenafil on diabetes-induced cardiac cell apoptosis and the antioxidant status of diabetic mouse hearts were investigated. Diabetic mice showed lower body weight gains and heart weights compared with control mice, and sildenafil treatment did not increase these parameters in diabetic mice. Although apoptotic rates, caspase-3 enzyme activity, and malondialdehyde levels were significantly higher in diabetic mouse hearts than in controls, they were reduced in diabetic mice after sildenafil treatment. At the end of the first week, we observed no significant differences in antioxidant enzyme activities (CAT, GSH-Px, and SOD) in diabetic and control groups, whereas at the end of the second week of sildenafil treatment, antioxidant enzyme activities were higher in the diabetic group. In conclusion, our study indicated that sildenafil was beneficial to hearts of diabetic mice by reducing cardiac cell apoptosis, partially because of its antioxidant effects in the heart.
Effects of enalapril and sodium depletion on the renin-angiotensin system in hydronephrotic mice
Authors: Zhang Yanling , Wu Junyan , Wang Xuechun , Morgan Trefor
Published: September 2009

The effects of enalapril and sodium depletion on renin synthesis and secretion were studied in mice with a left hydronephrotic kidney caused by unilateral ureteral ligation (UUL). In the control animals, there was no difference in plasma renin concentration between the right and left renal veins. In mice with left ureteral ligation, the renin concentration in the vein draining the hydronephrotic kidney was similar to or lower than that in the aorta under control conditions and after either stimulation with enalapril or depletion of sodium. Enalapril and sodium restriction increased plasma renin concentration, and this increase was due to secretion from the nonhydronephrotic kidney. The renin concentration per gram of kidney tissue and the mRNA for renin per gram of kidney tissue were similar in both the control and hydronephrotic kidney, and the values rose 3–4-fold in both kidneys after enalapril or sodium depletion. Immunostaining for renin confirmed these findings and indicated that renin per glomerulus was higher in the hydronephrotic kidney. Thus, removal or reduction of angiotensin II activity or depletion of sodium stimulated synthetic activity to a similar extent in the normal and hydronephrotic kidneys; however, secretion from the kidney without a macula densa (hydronephrotic) was not increased. Thus, the signals that control synthesis and secretion are different, and for these stimuli, secretion appears to require an intact macula densa.
Sex and hormonal influences on the nicotine-induced attenuation of isoprenaline vasodilations in the perfused rat kidney
Authors: El-Mas Mahmoud M. , El-Gowilly Sahar M. , Gohar Eman Y. , Ghazal Abdel-Rheem M.
Published: September 2009

We previously reported that nicotine impairs β-adrenoceptor-mediated renovascular control in male rats. Here, we investigated the roles of sex and estrogen in nicotine–β-adrenoceptor renal interaction. The effect of nicotine on renal vasodilations caused by isoprenaline was evaluated in phenylephrine-preconstricted perfused kidneys of male and proestrus female rats in absence and presence of NG-nitro-l-arginine (l-NNA, a NOS inhibitor). The interaction was also studied in diestrus and ovariectomized (OVX) rats treated with or without estradiol, tamoxifen, or l-arginine. Bolus isoprenaline (0.03–8.0 µmol) elicited dose-dependent renal vasodilations; female preparations were more sensitive (smaller ED50) to isoprenaline-induced vasodilation than were male preparations. Infusion of nicotine (500 µmol/L) reduced isoprenaline vasodilations in the 2 sexes and abolished male-female differences in isoprenaline responses. l-NNA reduced isoprenaline vasodilations in proestrus but not in male preparations. Also, in the presence of l-NNA, nicotine caused no attenuation of isoprenaline vasodilations in proestrus preparations. Renal responses to isoprenaline together with the attenuation of these responses by nicotine were reduced by OVX and restored to near-proestrus levels after supplementation with estradiol, the estrogen receptor modulator tamoxifen, or l-arginine. In diestrus rats, which exhibited reduced plasma estradiol, nicotine caused less attenuation of isoprenaline vasodilations. We conclude that impairment of estrogen–NOS signaling constitutes a possible cellular mechanism for the detrimental effect of nicotine on isoprenaline vasodilations in female rats. The mechanism of the nicotine-induced attenuation of isoprenaline vasodilation in male kidneys, which is NOS-independent, remains to be elucidated.
Rosiglitazone inhibits high glucose-induced apoptosis in human umbilical vein endothelial cells through the PI3K/Akt/eNOS pathway
Authors: Wu Jing , Lei Min-Xiang , Xie Xiao-Yun , Liu Lan , She Yan-Mei , Mo Juan , Wang Shan
Published: September 2009

Previous studies have shown that the phosphatidylinositol 3-kinase / Akt / endothelial nitric oxide synthase / NO (PI3K/Akt/eNOS/NO) pathway is involved in high glucose-induced endothelial cell apoptosis and rosiglitazone has a protective effect on endothelium. In the present study, we investigated the antiapoptotic effect of rosiglitazone on human umbilical vein endothelial cells (HUVECs) exposed to high glucose and explored its possible mechanism. Treatment of high glucose (33 mmol/L) for 48 h significantly induced the apoptosis of HUVECs, concomitantly with increased caspase-3 activity. High glucose treatment also decreased Akt and eNOS phosphorylation levels with subsequent NO production. All these alterations induced by high glucose were attenuated by rosiglitazone (1 µmol/L). Interestingly, the antiapoptotic effect of rosiglitazone was inhibited by PI3K inhibitor (LY294002, wortmannin) or eNOS inhibitor NG-l-nitro-arginine methyl ester (l-NAME). The reverse effects of rosiglitazone on phosphorylation of Akt and eNOS with subsequent NO production were also inhibited by LY294002, wortmannin or l-NAME, respectively. These findings suggest that rosiglitazone inhibits high glucose-induced apoptosis in HUVECs through the PI3K/Akt/eNOS pathway.
Role of the excessive amounts of circulating catecholamines and glucocorticoids in stress-induced heart disease
Authors: Adameova Adriana , Abdellatif Yasser , Dhalla Naranjan S.
Published: September 2009

Various stressful stimuli are known to activate the sympathetic nervous system to release catecholamines and the hypothalamic–pituitary–adrenal axis to release glucocorticoids in the circulation. Although initial actions of both catecholamines and glucocorticoids are beneficial for the function of the cardiovascular system, their delayed effects on the heart are deleterious. Glucocorticoids not only increase plasma levels of catecholamines by inhibiting their extraneuronal uptake, but they have also been shown to induce supersensitivity to catecholamines in the heart by upregulating different components of the β-adrenoceptor signal transduction system. Low concentrations of catecholamines stimulate the heart by promoting Ca2+movements, whereas excessive amounts of catecholamines produce cardiac dysfunction by inducing intracellular Ca2+overload in cardiomyocytes. Several studies have shown, however, that under stressful conditions high concentrations of catecholamines become oxidized to form aminolutins and generate oxyradicals. These oxidation products of catecholamines have been demonstrated to produce coronary spasm, arrhythmias, and cardiac dysfunction by inducing Ca2+-handling abnormalities in both sarcolemmal and sarcoplasmic reticulum, defects in energy production by mitochondria, and myocardial cell damage. In this article we have focused the discussion to highlight the interrelationship between catecholamines and glucocorticoids and to emphasize the role of oxidation products of catecholamines in the development of stress-induced heart disease.
Lateral-line activity during undulatory body motions suggests a feedback link in closed-loop control of sea lamprey swimming
Authors: Ayali A. , Gelman S. , Tytell E. D. , Cohen A. H.
Published: September 2009

The lateral-line system is common to most aquatic organisms. It plays an important role in behaviours involving detection of other animals and obstacles. In gnathostome fishes, these behaviours appear to be dependent on an efferent inhibitory system that filters out stimuli caused by the animal’s own movement. Sea lampreys ( Petromyzon marinus L., 1758), the most basal extant vertebrate, possess a functional lateral-line system. Yet they completely lack the inhibitory efferent system. Thus, they may use the lateral line to sense their own swimming movements, helping to stabilize swimming. To test this hypothesis, we first investigated the kinematics of free-swimming lampreys. In an intact tethered preparation, we then generated undualatory body motions of comparable amplitude and frequency to swimming, while monitoring the evoked responses of the posterior lateral-line nerve. Last, we tested the effect of eliminating lateral-line inputs by cobalt treatment. In the tethered preparation, we recorded distinctive and consistent activity in the lateral-line nerve that was strongly dependent on characteristics of the motion. We found that distinct characteristics of the rhythmic movements are encoded in the temporal characteristics of the response. Swimming kinematics of cobalt-treated animals differed from controls, suggesting a complex, yet necessary role of the lateral-line system in closed-loop control of swimming.
Influence of alternative mating tactics on predation risk in the damselfly Calopteryx virgo
Authors: Toivanen Tero , Rantala Markus J. , Suhonen Jukka
Published: September 2009

Alternative mating tactics are a widespread feature in insects. A typical form of alternative mating behaviour is being a sneaker in the vicinity of a territorial male. Such nonterritorial males have lower mating success, but they may benefit from lower energetic costs and decreased predation risk. In this study, we examined whether nonterritorial male damselflies Calopteryx virgo (L., 1758) are subject to lower predation risk than territorial males. To distinguish predation from other sources of mortality, we used models. The experiment consisted of dried male damselflies settled into the typical perching positions of territorial and nonterritorial males. Also the spatiotemporal patterns of predation risk were studied. The survival of nonterritorial male models was consistently higher than that of territorial male models, which can be attributed to different predation risk. Survival of the models was lower in the presence of avian predators and in large populations. Survival rates were affected by habitat type but did not change during the season. We conclude that nonterritorial male damselflies are less vulnerable to predation and that there may be a trade-off which could potentially make the fitness of sneakers equal to that of territorial males.
Molecular and morphological evidence for a new species status within the genus Euseius (Acari: Phytoseiidae)
Authors: Okassa M. , Tixier M.-S. , Cheval B. , Kreiter S.
Published: September 2009

The identity of specimens belonging to the genus Euseius Wainstein, 1962 found on several trees in France is investigated. These specimens are morphologically close to Euseius stipulatus (Athias-Henriot, 1960) except for the shape of the spermatheca and the dorsal shield reticulation. The aim of the present study was to determine if these specimens belong to this latter species and if the shape of the spermatheca could be considered a reliable diagnostic character. Thirty-four characters, including idiosomal seta lengths, were measured and molecular tests (12S rDNA, COI mtDNA) were carried out. Although small, significant differences between populations of Euseius sp. were observed. The morphometric differences between E. stipulatus and Euseius sp. were very small except for the seta z2 and for the length of the ventrianal shield, as well as the length and form of the spermatheca. Molecular analyses support that Euseius sp. and E. stipulatus are two different species. Euseius sp. has been described as a new species to science in another publication under the name Euseius gallicus . Reliability of some morphological characters for species diagnosis is discussed.
Influence of the environmental heterogeneity of breeding ponds on anuran assemblages from southeastern Brazil
Authors: Vasconcelos T. S. , Santos T. G. , Rossa-Feres D. C. , Haddad C.F.B
Published: September 2009

We hypothesized that the environmental heterogeneity of breeding ponds influences the species composition and species richness of anuran assemblages from southeastern Brazil, because it provides humidity, shelter, and breeding microhabitats for anuran species, which can result in an increasing number of species in a given habitat. To begin, we tested whether the occurrence of anuran species in each breeding pond is different from a null model of random placement of species in those ponds. We then performed two tests to evaluate which of the five environmental descriptors of breeding ponds influence (1) the species composition and (2) species richness. Species composition of the 38 breeding ponds was correlated with number of edge types, number of plant types along the edges of the breeding ponds, and the hydroperiod. Neither the percentage of vegetation cover on the water’s surface nor the size of the breeding ponds were correlated with species composition. Only the number of edge types was correlated with species richness of breeding ponds. The correlation of three environmental descriptors with species composition and one environmental descriptor with species richness, as well as the high beta diversity among breeding ponds, suggest that the analyses of environmental heterogeneity on species composition was more informative than was the analysis for species richness, because breeding ponds with similar species richness can have distinct species composition among them (high beta diversity).
Parasitism, mercury contamination, and stable isotopes in fish-eating double-crested cormorants: no support for the co-ingestion hypothesis
Authors: Robinson S. A. , Forbes M. R. , Hebert C. E.
Published: September 2009

Mercury and parasitism have been positively correlated in free-ranging birds. One proposed explanation is that mercury reduces host immunity, resulting in a greater susceptibility to parasitism. However, alternative explanations should be addressed to further inform and test hypotheses about relationships between mercury and parasitism. We investigated whether total mercury and Contracaecum spp. were correlated in double-crested cormorants ( Phalacrocorax auritus (Lesson, 1831)) and whether there was support for mercury and infective stages of parasites being co-ingested. For breeding cormorants, males had 1.5 times more total mercury in breast muscle than did females and >2 times more Contracaecum spp. in the proventriculus and stomach region. Males responsible for the sex biases in mercury concentration were not the same males responsible for sex biases in parasitism, hence separate explanations for these patterns were required. Males foraged in more pelagic areas and at a slightly lower trophic level than did females, as determined by stable C and N isotope signatures, respectively. These sex differences in foraging and expected differential consumption of intermediate fish hosts could explain the sex bias in parasitism but not the sex bias in mercury concentration. We suggest when testing contaminant–parasite linkages that sex differences in exposure be addressed.
The female reproductive system and control of oviposition in Locusta migratoria migratorioidesThe present review is the first of a series of occasional review articles that have been invited by the Editors and will feature the broad range of disciplines and expertise represented in our Editorial Advisory Board.
Authors: Lange Angela B.
Published: September 2009

The spermatheca acts as a repository for sperm deposited by the male and, in the African migratory locust ( Locusta migratoria migratorioides (Fairmaire and Reiche, 1849)), is situated dorsal to the lateral and common oviducts. In the locust, eggs mature in the ovaries and are ovulated into the lateral oviducts where they are held until a suitable oviposition site is found. At that time, a hole is dug in the soil by the locust and, aided by muscular contractions of the upper lateral oviducts, the eggs are propelled through the common oviduct and genital chamber and deposited in a pod in the soil. Contractions of the spermathecal sac lead to sperm release, resulting in fertilization of eggs in the genital chamber. Coordination of digging and of the oviducts and spermatheca is clearly critical to the production of viable eggs. The muscles responsible for digging and both reproductive structures are under central neuronal control, incorporating neurons that express an array of neuropeptide and amine phenotypes. Many of the phenotypes are common to both reproductive tissues. A neural loop ensures the coordinated release of sperm when an egg passes into the genital chamber. This review will discuss our understanding of the neural control of these reproductive tissues and their coordination with digging.
Female effect on antlers of pampas deer (Ozotoceros bezoarticus)
Authors: Ungerfeld R. , Damián J. P. , Villagrán M. , González-Pensado S. X.
Published: September 2009

Size and bone mineralization of deer antlers are related to testosterone concentrations, and antler cast is observed after withdrawal of testosterone concentration. Our objectives were to determine if (i) contact with hinds stimulates antler development and increases hard antler period length in pampas deer ( Ozotoceros bezoarticus (L., 1758)) and (ii) antlers from males that were or were not in contact with hinds differ in colour. While 5 males were in breeding paddocks consisting of 1 adult stag and 5–10 hinds, the other 6 males were allocated as a single-male group. We collected, weighed, and measured the volume, circumferences, and lengths of antlers, and determined their colour. First antler cast tended to be later in males in contact with females than those in the single-male group. Antler mass and volume were greater in antlers from males in contact with females. Circumference at the base of first and second tines was also greater in antlers collected from males in contact with females. Surfaces of antlers from these males were darker than those of antlers from males that remained isolated from females in all points. Hind contact stimulated male pampas deer, increasing antler mass, size, and darkness, as well as possibly hard antler period length.
Investigating virtual passthrough I/O on commodity devices
Authors: Xia Lei , Lange Jack , Dinda Peter , Bae Chang
Published: September 2009

A commodity I/O device has no support for virtualization. A VMM can assign such a device to a single guest with direct, fast, but insecure access by the guest's native device driver. Alternatively, the VMMcan build virtual devices on top of the physical device, allowing it to be multiplexed across VMs, but with lower performance. We propose a technique that provides an intermediate option. In virtual passthrough I/O (VPIO), the guest interacts directly with the physical device most of the time, achieving high performance, as in passthrough I/O. Additionally, the guest/device interactions drive a model that in turn identifies (1) when the physical device can be handed off to another VM, and (2) if the guest programs the device to behave illegitimately. In this paper, we describe the VPIO model, and present preliminary results in using it to support two commodity network cards within the Palacios VMM we are building. We believe that an appropriate model for an I/O device could be produced by the hardware vendor as part of the design, implementation, and testing process.
Server virtualization architecture and implementation
Authors: Daniels Jeff
Published: September 2009

Virtual machine technology, or virtualization, is gaining momentum in the information technology community. While virtual machines are not a new concept, recent advances in hardware and software technology have brought virtualization to the forefront of IT management. Stability, cost savings, and manageability are among the reasons for the recent rise of virtualization. Virtual machine solutions can be classified by hardware, software, and operating system/containers. From its inception on the mainframe to distributed servers on x86, the virtual machine has matured and will play an increasing role in systems management.
Effects of progesterone on motility and prostaglandin levels in the distal guinea pig colon
Authors: Xiao Zuo Liang , Biancani Piero , Behar Jose
Published: September 2009

Progesterone (P4) inhibits the gastrointestinal muscle contraction by downregulating Gαq/11proteins that mediate contraction, by upregulating Gαsproteins that mediate relaxation, and by altering the pattern of cyclooxygenase (COX) enzymes and prostaglandins. We aimed to examine whether P4 treatment of guinea pigs in vivo affects basal colon motility [basal motility index (MI)] by altering the levels and actions of PGF2αand PGE2. Guinea pigs were treated with intramuscular (IM) P4 for 4 days. The BASAL MI, the PGF2α-induced contraction, and PGE2-induced inhibition of contraction were examined in muscle strips and cells. The levels of PGF2αand PGE2were measured by radioimmunoassay. Treatment with P4 reduced the basal MI, the levels of PGF2α, and PGF2α-induced contraction. P4 increased PGE2levels, and PGE2induced relaxation. Pretreatment with IM RU-486 (10 mg/kg per day), a P4 receptor antagonist, 1 h before P4 blocked the actions of P4. The PGF2αantagonist Al-1180 abolished basal MI and PGF2α-induced contraction. N-ethylmaleimide, which blocks unoccupied membrane receptors, blocked Ach and VIP actions but had no effect on PGF2αand PGE2effects. A COX-1 inhibitor decreased and a COX-2 inhibitor increased PGF2αlevels; GTPγS increased and GDPβS decreased the levels of PGF2α. Gαq/11protein antibodies (Abs) reduced PGF2αlevels, and Gαi3Abs blocked its motor actions. Gαs Abs increased PGF2αbut decreased PGE2levels. We concluded that P4 decreases basal MI by reducing PGF2αlevels caused by downregulation of Gαq/11and that PGF2α-induced contraction was blocked by downregulating Gαi3. P4 also decreased the basal MI by increasing PGE2levels, and PGE2induced relaxation by upregulating Gαsproteins.
The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs
Authors: Urquhart Bradley L. , Gregor Jamie C. , Chande Nilesh , Knauer Michael J. , Tirona Rommel G. , Kim Richard B.
Published: September 2009

Folic acid is a vitamin essential for thymidylate and purine synthesis. The human proton-coupled folate transporter (hPCFT) has recently been identified as a pH-dependent folic acid transporter, and mutations in this transporter have been linked to hereditary folic acid malabsorption. In this study, we assessed hPCFT-mediated transport activity in vitro, intersubject variability of intestinal expression in relation to blood folates, and the relationship of proton-pump inhibitor (PPI) therapy on hPCFT expression in vivo. We created a Madin-Darby canine kidney strain II (MDCKII) cell line stably expressing hPCFT to evaluate its drug substrates and inhibitors. Intestinal pinch biopsies (duodenum, ileum, colon) were collected from patients undergoing routine endoscopy procedures, and expressed levels of hPCFT were determined by RT-PCR. When assessed using MDCKII-hPCFT cells, folic acid and methotrexate were found to be high-affinity hPCFT substrates. Sulfasalazine and pyrimethamine were noted to inhibit hPCFT activity with Ki values of 42.3 and 161.7 μmol/l, respectively. hPCFT was localized to the brush-border membrane of enterocytes with highest expression in the duodenum and reduced levels in the ileum and colon. When we assessed hPCFT expression in a subset of patients who were receiving PPI therapy, a near 50% reduction in duodenal hPCFT mRNA expression was noted. These results suggest that hPCFT transporter activity can be modulated by many drugs in clinical use, and expression of this transporter in the gastrointestinal tract is higher in the duodenum than more distal sites (duodenum > ileum > colon). Importantly, we note that PPI drug use appears to be associated with reduced hPCFT expression in vivo.
Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family
Authors: Ohno Izumi , Eibl Guido , Odinokova Irina , Edderkaoui Mouad , Damoiseaux Robert D. , Yazbec Moussa , Abrol Ravinder , Goddard William A. , Yokosuka Osamu , Pandol Stephen J. , Gukovskaya Anna S.
Published: September 2009

Rottlerin is a polyphenolic compound derived from Mallotus philipinensis . In the present study, we show that rottlerin decreased tumor size and stimulated apoptosis in an orthotopic model of pancreatic cancer with no effect on normal tissues in vivo. Rottlerin also induced apoptosis in pancreatic cancer (PaCa) cell lines by interacting with mitochondria and stimulating cytochrome c release. Immunoprecipitation results indicated that rottlerin disrupts complexes of prosurvival Bcl-xL with Bim and Puma. Furthermore, siRNA knockdown showed that Bim and Puma are necessary for rottlerin to stimulate apoptosis. We also showed that rottlerin and Bcl-2 and Bcl-xL inhibitor BH3I-2′ stimulate apoptosis through a common mechanism. They both directly interact with mitochondria, causing increased cytochrome c release and mitochondrial depolarization, and both decrease sequestration of BH3-only proteins by Bcl-xL. However, the effects of rottlerin and BH3I-2′ on the complex formation between Bcl-xL and BH3-only proteins are different. BH3I-2′ disrupts complexes of Bcl-xL with Bad but not with Bim or Puma, whereas rottlerin had no effect on the Bcl-xL interaction with Bad. Also BH3I-2′, but not rottlerin, required Bad to stimulate apoptosis. In conclusion, our results demonstrate that rottlerin has a potent proapoptotic and antitumor activity in pancreatic cancer, which is mediated by disrupting the interaction between prosurvival Bcl-2 proteins and proapoptotic BH3-only proteins. Thus rottlerin represents a promising novel agent for pancreatic cancer treatment.
Antioxidants and aging: NMR-based evidence of improved skeletal muscle perfusion and energetics
Authors: Wray D. Walter , Nishiyama Steven K. , Monnet Aurélien , Wary Claire , Duteil Sandrine S. , Carlier Pierre G. , Richardson Russell S.
Published: September 2009

We sought to examine the potential role of oxidative stress on skeletal muscle function with advancing age. Nuclear magnetic resonance (NMR) was employed to simultaneously assess muscle perfusion (arterial spin labeling) and energetics (31P NMR spectroscopy) in the lower leg of young (26 ± 5 yr, n = 6) and older (70 ± 5 yr, n = 6) healthy volunteers following the consumption of either placebo (PL) or an oral antioxidant (AO) cocktail (vitamins C and E and α-lipoic acid), previously documented to decrease plasma free radical concentration. NMR measurements were made during and after 5 min of moderate intensity (≈5 W) plantar flexion exercise. AO administration significantly improved end-exercise perfusion (AO, 50 ± 5, and PL, 43 ± 4 ml·100 g−1·min−1) and postexercise perfusion area under the curve (AO, 1,286 ± 236, and PL, 866 ± 144 ml/100 g) in older subjects, whereas AO administration did not alter hemodynamics in the young group. Concomitantly, muscle oxidative capacity (time constant of phosphocreatine recovery, τ) was improved following AO in the older (AO, 43 ± 1, and PL, 51 ± 7 s) but not the young (AO, 54 ± 5, and PL, 48 ± 7 s) group. These findings support the concept that oxidative stress may be partially responsible for the age-related decline in skeletal muscle perfusion during physical activity and reveal a muscle metabolic reserve capacity in the elderly that is accessible under conditions of improved perfusion.
Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass
Authors: Ryou Myoung-Gwi , Flaherty Devin C. , Hoxha Besim , Sun Jie , Gurji Hunaid , Rodriguez Steven , Bell Glenn , Olivencia-Yurvati Albert H. , Mallet Robert T.
Published: September 2009

Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the α-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose ± 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1α, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1α, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia ( P < 0.05). Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium ( P < 0.01), but did not alter Akt phosphorylation. Nitric oxide synthase (NOS) activity and eNOS content fell 32% following control CPB vs. sham, but pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values ( P < 0.01). Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1α, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.
Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways
Authors: Zhang Meng , Lin Ling , Lee Seon-Jin , Mo Li , Cao Jiaofei , Ifedigbo Emeka , Jin Yang
Published: September 2009

Hyperoxia-induced lung injury is an established model that mimics human acute respiratory distress syndrome. Cell death is a prominent feature in lungs following prolonged hyperoxia. Caveolae are omega-shaped invaginations of the plasma membrane. Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. We have recently shown that deletion of cav-1 (cav-1−/−) protected against hyperoxia-induced cell death and lung injury both in vitro and in vivo; however, the mechanisms remain unclear. Survivin, a member of the inhibitor of apoptosis protein family, inhibits apoptosis in tumor cells. Although emerging evidence suggests that survivin is involved in wound healing, especially in vascular injuries, its role in hyperoxia-induced lung injury has not been investigated. Our current data demonstrated that hyperoxia induced apoptosis via suppressing survivin expression. Deletion of cav-1 abolished this suppression and subsequently protected against hyperoxia-induced apoptosis. Using “gain” and “loss” of function assays, we determined that survivin protected lung cells from hyperoxia-induced apoptosis via the inhibition of apoptosis executor caspase-3. Overexpression of survivin by deletion of cav-1 was regulated by Egr-1. Egr-1 functioned as a negative regulator of survivin expression. Deletion of cav-1 upregulated survivin via decreased Egr-1 binding of the survivin promoter region. Together, this study illustrates the effect of hyperoxia on survivin expression and the role of survivin in hyperoxia-induced apoptosis. We also demonstrate that deletion of cav-1 protects hyperoxia-induced apoptosis via modulation of survivin expression.
Effect of contrasting physical exercise interventions on rapid force capacity of chronically painful muscles
Authors: Andersen Lars L. , Andersen Jesper L. , Suetta Charlotte , Kjær Michael , Søgaard Karen , Sjøgaard Gisela
Published: September 2009

Rapid force capacity of chronically painful muscles is inhibited markedly more than maximal force capacity and is therefore relevant to assess in rehabilitation settings. Our objective was to investigate the effect of two contrasting types of physical exercise on rapid force capacity, as well as neural and muscular adaptations in women with chronic neck muscle pain. A group of employed women ( n = 42) with a clinical diagnosis of trapezius myalgia participated in a 10-wk randomized controlled trial; specific strength training of the neck/shoulder muscles, general fitness training performed as leg-bicycling; or a reference intervention without physical activity. Maximal voluntary shoulder abductions were performed at static angles of 35° and 115° with simultaneous recording of electromyography (EMG) in the trapezius and deltoid. Maximal muscle strength and activation (peak torque and peak EMG) as well as rapid muscle strength and activation [rate of torque development (RTD) and rate of EMG rise] were subsequently determined. Trapezius muscle fiber characteristics were determined with ATPase histochemistry. Significant changes were observed only in the specific strength training group. Whereas peak torque increased 18–29% ( P < 0.01), RTD increased 61–115% ( P < 0.001). Peak EMG and rate of EMG rise increased correspondingly ( P < 0.05–0.001), and trapezius type II muscle fibers hypertrophied 20% ( P < 0.001). In conclusion, rapid force capacity of chronically painful muscles is highly responsive to rehabilitation with specific strength training. The underlying mechanisms were related to both pain reduction and general neuromuscular adaptations to strength training. Potentially, the present method can be a useful clinical screening tool of muscle function in rehabilitation settings.
Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers
Authors: Sheel A. William , Guenette Jordan A. , Yuan Ren , Holy Lukas , Mayo John R. , McWilliams Annette M. , Lam Stephen , Coxson Harvey O.
Published: September 2009

We sought to determine the relationship between lung size and airway size in men and women of varying stature. We also asked if men and women matched for lung size would still have differences in airway size and if so where along the pulmonary airway tree would these differences exist. We used computed tomography to measure airway luminal areas of the large and central airways. We determined airway luminal areas in men ( n = 25) and women ( n = 25) who were matched for age, body mass index, smoking history, and pulmonary function and in a separate set of men ( n = 10) and women ( n = 11) who were matched for lung size. Men had greater values for the larger airways and many of the central airways. When male and female subjects were pooled there were significant associations between lung size and airway size. Within the male and female groups the magnitudes of these associations were decreased or nonsignificant. In males and females matched for lung size women had significantly smaller airway luminal areas. The larger conducting airways in females are significantly smaller than those of males even after controlling for lung size.
Combined Therapy With Simvastatin and Bone Marrow–Derived Mesenchymal Stem Cells Increases Benefits in Infarcted Swine Hearts
Authors: Yang Yue-Jin , Qian Hai-Yan , Huang Ji , Li Jian-Jun , Gao Run-Lin , Dou Ke-Fei , Yang Guo-Sheng , Willerson James T. , Geng Yong-Jian
Published: September 2009

Objective—

Widespread death of implanted cells hampers stem cell therapy for acute myocardial infarction (AMI). Based on the pleiotropic beneficial effects of statins, we examined whether simvastatin (SIMV) increased the efficacy of mesenchymal stem cell (MSC) transplantation after AMI.

Methods and Results—

Chinese miniswine (n=28) were randomized to 1 of 4 groups (n=7 per group): control, SIMV (0.25 mg/kg · d), MSC transplantation, and SIMV+MSCs. AMI was created by ligating the left anterior descending coronary artery; MSCs were injected immediately into the cyanotic myocardium. At 6 weeks, MRI showed the number of dyskinetic segments and the infarct size were significantly decreased in the SIMV group. Cardiac function improved and the perfusion defect decreased significantly in the SIMV+MSC group but not in the MSC-only group (
P
<0.05, versus control group). MSC survival and differentiation were significantly better in the combination group than in the MSC-only group (
P
<0.01). Cell apoptosis decreased significantly in both the SIMV and the SIMV+MSC groups but not in the MSC-only group when compared with controls (
P
<0.05). Furthermore, oxidative stress and inflammatory response was significantly reduced in the infarcted regions in both the SIMV and the SIMV+MSCs groups.

Conclusions—

SIMV treatment improves the therapeutic efficacy of MSC transplantation in acutely infarcted hearts by promoting cell survival and cardiovascular differentiation.
PCSK9 Dominant Negative Mutant Results in Increased LDL Catabolic Rate and Familial Hypobetalipoproteinemia
Authors: Cariou Bertrand , Ouguerram Khadija , Zaïr Yassine , Guerois Raphael , Langhi Cédric , Kourimate Sanae , Benoit Isabelle , Le May Cédric , Gayet Constance , Belabbas Khaldia , Dufernez Fabienne , Chétiveaux Maud , Tarugi Patrizia , Krempf Michel , Benlian Pascale , Costet Philippe
Published: September 2009

Objective—

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central player in the regulation of cholesterol homeostasis, increasing the low-density lipoprotein (LDL) receptor degradation. Our study aimed at exploring the pathogenic consequences in vivo and in vitro of a PCSK9 prodomain mutation found in a family with hypobetalipoproteinemia (FHBL).

Methods and Results—

A white 49-year-old diabetic man had profound FBHL (LDLC: 16 mg/dL) whereas his daughter and sister displayed a milder phenotype (LDLC 44 mg/dL and 57 mg/dL, respectively), all otherwise healthy with a normal liver function. A monoallelic
PCSK9
double-mutant R104C/V114A cosegregated with FBHL, with no mutation found at other FHBL-causing loci. A dose-effect was also found in FBHL relatives for plasma APOB and PCSK9 (very-low to undetectable in proband, ≈50% decreased in sister and daughter) and LDL catabolic rate (256% and 88% increased in proband and daughter). Transient transfection in hepatocytes showed severely impaired processing and secretion of the double mutant which acted as a dominant negative over secretion of wild-type PCSK9.

Conclusion—

These results show that heterozygous PCSK9 missense mutations may associate with profound hypobetalipoproteinemia and constitute the first direct evidence in human that decrease of plasma LDLC concentrations associated to PCSK9 LOF mutations are attributable to an increased clearance rate of LDL.
Matrix Metalloproteinase-10 Is Upregulated by Thrombin in Endothelial Cells and Increased in Patients With Enhanced Thrombin Generation
Authors: Orbe Josune , Rodríguez José A. , Calvayrac Olivier , Rodríguez-Calvo Ricardo , Rodríguez Cristina , Roncal Carmen , Martínez de Lizarrondo Sara , Barrenetxe Jaione , Reverter Juan C. , Martínez-González José , Páramo José A.
Published: September 2009

Objective—

Thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated.

Methods and Results—

Thrombin induced endothelial MMP-10 mRNA and protein levels, through a protease-activated receptor-1 (PAR-1)–dependent mechanism, in a dose- and time-dependent manner. This effect was mimicked by a PAR-1 agonist peptide (TRAP-1) and antagonized by an anti–PAR-1 blocking antibody. MMP-10 induction was dependent on extracellular regulated kinase1/2 (ERK1/2) and c-jun N-terminal kinase (JNK) pathways. By serial deletion analysis, site-directed mutagenesis and electrophoretic mobility shift assay an AP-1 site in the proximal region of MMP-10 promoter was found to be critical for thrombin-induced MMP-10 transcriptional activity. Thrombin and TRAP-1 upregulated MMP-10 in murine endothelial cells in culture and in vivo in mouse aorta. This effect of thrombin was not observed in PAR-1–deficient mice. Interestingly, circulating MMP-10 levels (
P
<0.01) were augmented in patients with endothelial activation associated with high (disseminated intravascular coagulation) and moderate (previous acute myocardial infarction) systemic thrombin generation.

Conclusion—

Thrombin induces MMP-10 through a PAR-1–dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Endothelial MMP-10 upregulation could be regarded as a new proinflammatory effect of thrombin whose pathological consequences in thrombin-related disorders and plaque stability deserve further investigation.
Fn14-Fc Fusion Protein Regulates Atherosclerosis in ApoE
−/−
Mice and Inhibits Macrophage Lipid Uptake In Vitro
Authors: Schapira Kitty , Burkly Linda C. , Zheng Timothy S. , Wu Ping , Groeneweg Mathijs , Rousch Mat , Kockx Mark M. , Daemen Mat J.A.P. , Heeneman Sylvia
Published: September 2009

Objective—

TWEAK is a multifunctional cytokine belonging to the tumor necrosis factor superfamily and binds to the receptor Fn14. TWEAK and Fn14 are expressed in atherosclerotic plaques in areas rich in macrophages and foam cells. We investigated the role of TWEAK/Fn14 interactions in ApoE
−/−
mice and bone marrow–derived macrophages in vitro.

Methods and Results—

ApoE
−/−
mice were treated with TWEAK-inhibiting fusion protein, Fn14-Fc, in an early (5 to 17 weeks of age) or delayed (17 to 29 weeks of age) setting. In the aortic arch, Fn14-Fc as compared to control treatment resulted in advanced plaques which were smaller (early treatment), fewer (delayed treatment), lower in fibrotic content (early and delayed treatment), and exhibited an increased macrophage content and smaller macrophage size (delayed treatment). There were no differences in apoptosis in atherosclerotic plaques after Fn14-Fc versus control Ab treatment. However, blocking TWEAK resulted in less macrophage uptake of modified lipids in vitro.

Conclusions—

Fn14-Fc fusion protein treatment did not prevent lesion initiation but inhibited some features of plaque progression and induced a unique advanced plaque phenotype with increased macrophage content and smaller macrophage size, which may be attributable to reduced lipid uptake. These findings indicate that TWEAK/Fn14 interactions regulate atherosclerosis and mediate lipid uptake in macrophages.
Sudden Infant Death Syndrome in Mice With an Inherited Mutation in
RyR2
Authors: Mathur Nitin , Sood Subeena , Wang Sufen , van Oort Ralph J. , Sarma Satyam , Li Na , Skapura Darlene G. , Bayle J. Henri , Valderrábano Miguel , Wehrens Xander H.T.
Published: September 2009

Background—

Mutations in the cardiac ryanodine receptor gene (
RyR2
) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in
RyR2
increases the propensity to cardiac arrhythmias and sudden death in young mice.

Methods and Results—

Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in
RyR2
(R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription–polymerase chain reaction and Western blotting showed that expression levels of other calcium handling proteins were unaltered, suggesting that calcium leak through mutant
RyR2
underlies arrhythmogenesis and sudden death in young R176Q/+ mice.

Conclusions—

Our findings demonstrate that a gain-of-function mutation in
RyR2
confers an increased risk of cardiac arrhythmias and sudden death in young mice and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with sudden infant death syndrome.
Safety of Binodenoson, a Selective Adenosine A2AReceptor Agonist Vasodilator Pharmacological Stress Agent, in Healthy Subjects With Mild Intermittent Asthma
Authors: Murray John J. , Weiler John M. , Schwartz Lawrence B. , Busse William W. , Katial Rohit K. , Lockey Richard F. , McFadden E.R. , Pixton Glenn C. , Barrett Richard J.
Published: September 2009

Background—The pharmacological stress agents adenosine and dipyridamole are contraindicated in asthma patients because of the risk of adenosine receptor-mediated bronchospasm. Binodenoson, a selective adenosine A2Areceptor agonist, produces maximal coronary hyperemia during pharmacological stress testing yet has a low affinity for the adenosine A1, A2B, and A3receptors that are probably responsible for bronchospasm. This study was conducted to assess the safety of binodenoson in 87 healthy young adult volunteers with documented mild, intermittent asthma.

Methods and Results—This study consisted of a dose-escalating, single-blinded phase and a placebo-controlled, double-blinded phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blinded phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 μg/kg). In the double-blinded phase, commenced after medical review of results from the single-blinded phase, subjects were randomly assigned 2:1 to either binodenoson 1.5 μg/kg (n=41) or placebo (n=22). The primary end point was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second of ≥20% from the preinjection measure. Secondary safety end points were changes from preinjection measure in forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow during the middle 50% of the forced vital capacity; vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing.

Conclusions—Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.