Atorvastatin increases oxidative stress and modulates angiogenesis in Ossabaw swine with the metabolic syndrome

ObjectiveThe purpose of the present study was to evaluate the effect of atorvastatin on oxidative stress and angiogenesis in ischemic myocardium in a clinically relevant porcine model of the metabolic syndrome.MethodsSixteen Ossabaw pigs were fed either a high-fat diet alone or a high-fat diet supplemented with atorvastatin (1.5 mg/kg daily) for 14 weeks. Chronic myocardial ischemia was induced by ameroid constrictor placement around the circumflex artery. After 6 months of the diet, myocardial perfusion was measured at rest and with demand pacing. The heart was harvested for analysis of perfusion, microvessel relaxation, protein expression, and oxidative stress.ResultsBoth groups had similar endothelium-dependent microvessel relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside. Myocardial perfusion in the ischemic territory was also not significantly different either at rest or with demand pacing. Atorvastatin treatment increased total myocardial protein oxidation and serum lipid peroxidation. However, the expression of markers of oxidative stress, including NOX2, RAC1, myeloperoxidase, and superoxide dismutase 1, 2, and 3, were not statistically different. The expression of proangiogenic proteins endothelial nitric oxide synthase, phosphorylated endothelial nitric oxide synthase (Ser 1177), phosphorylated adenosine monophosphate kinase (Thr 172), phosphorylated extracellular signal-regulated kinase (T202, Y204), and vascular endothelial growth factor were all upregulated in the atorvastatin group.ConclusionsAtorvastatin increased the capillary and arteriolar density and upregulated the proangiogenic proteins endothelial nitric oxide synthase and phosphorylated endothelial nitric oxide synthase, phosphorylated adenosine monophosphate kinase, phosphorylated extracellular signal-regulated kinase, and vascular endothelial growth factor in a swine model of the metabolic syndrome. However, it failed to increase myocardial perfusion. Atorvastatin treatment was associated with increased myocardial and serum oxidative stress, which might contribute to the lack of collateral-dependent perfusion in the setting of angiogenesis

Hypercholesterolemia and chronic ischemia alter myocardial responses to selective cyclooxygenase-2 inhibition

ObjectiveCyclooxygenase-2 inhibitors have been implicated in adverse cardiac events. We hypothesize that hypercholesterolemia and ischemia may alter the myocardial response to the cyclooxygenase-2 inhibitor celecoxib.MethodsYorkshire swine fed normal chow (CX, n = 6) or high-cholesterol diet (HCX, n = 6) underwent placement of an Ameroid constrictor on the left circumflex artery and were started on celecoxib (200 mg/day). After 7 weeks, ischemic and nonischemic myocardium was analyzed for thrombogenic ratio (thromboxane content divided by prostacyclin content), total protein oxidative stress, and expression of prostacyclin synthase, thromboxane synthase, myeloperoxidase, and superoxide dismutase. Cardiac function, tissue perfusion, and vessel density were measured.ResultsHCX animals were significantly hypercholesterolemic compared with CX animals. Thrombogenic ratio was significantly higher in the HCX group than in the CX group, but prostacyclin and thromboxane synthase expression was similar in all tissues. Myocardial perfusion was decreased in the HCX group compared with the CX group. Total oxidative stress, myeloperoxidase, and superoxide dismutase were increased in ischemic tissue compared with nonischemic tissues, but there was no diet-induced difference between groups. There was no difference in capillary or arteriolar density between groups. Left ventricular contractility was greater in the HCX group than in the CX group, but there was no significant difference in heart rate, mean arterial pressure, or left ventricular pressure.ConclusionsHypercholesterolemic patients using celecoxib may be at higher risk for thrombotic events than those with normal cholesterol, but the relationship between dyslipidemia, ischemia, and cyclooxygenase-2 inhibition is likely much more complicated than originally thought

Metabolic Syndrome Impairs Notch Signaling and Promotes Apoptosis in Chronically Ischemic Myocardium

Objective Impaired angiogenesis is a known consequence of metabolic syndrome (MetS), however, the mechanism is not fully understood. Recent studies have shown that the Notch signaling pathway is an integral component of cardiac angiogenesis. We tested in a clinically relevant swine model the effects of MetS on Notch and apoptosis signaling in chronically ischemic myocardium. Methods Ossabaw swine were fed either a regular diet (CTL, n=8) or a high-cholesterol diet (MetS, n=8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, animals underwent cardiac harvest of the ischemic myocardium. Results There was down-regulation of pro-angiogenesis proteins Notch2, Notch4, Jagged2, Ang1 and ENOS in the MetS group compared to CTL. There was also up-regulation of pro-apoptosis protein Caspase8, and down-regulation of anti-angiogenesis protein pFOX03, and pro-survival proteins pP38 and HSP90 in the MetS group. Cell death was increased in the MetS group compared to CTL. Both CTL and MetS groups had similar arteriolar count and capillary density, and Notch3 and Jagged1 were both similarly concentrated in the smooth muscle wall in both groups. Conclusions MetS in chronic myocardial ischemia significantly impairs Notch signaling by down regulating Notch receptors, ligands and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, thus suggesting that inhibition of Notch signaling may underlie decreased angiogenesis in later stages of MetS

Traveling-Wave Tubes

Contains reports on four research projects

Asymptotically Matched Spacetime Metric for Non-Precessing, Spinning Black Hole Binaries

We construct a closed-form, fully analytical 4-metric that approximately represents the spacetime evolution of non-precessing, spinning black hole binaries from infinite separations up to a few orbits prior to merger. We employ the technique of asymptotic matching to join a perturbed Kerr metric in the neighborhood of each spinning black hole to a near-zone, post-Newtonian metric farther out. The latter is already naturally matched to a far-zone, post-Minkowskian metric that accounts for full temporal retardation. The result is a 4-metric that is approximately valid everywhere in space and in a small bundle of spatial hypersurfaces. We here restrict our attention to quasi- circular orbits, but the method is valid for any orbital motion or physical scenario, provided an overlapping region of validity or buffer zone exists. A simple extension of such a metric will allow for future studies of the accretion disk and jet dynamics around spinning back hole binaries

Mutations in Arabidopsis \u3ci\u3eYellow Stripe-Like1\u3c/i\u3e and \u3ci\u3eYellow Stripe-Like3\u3c/i\u3e Reveal Their Roles in Metal Ion Homeostasis and Loading of Metal Ions in Seeds

Here, we describe two members of the Arabidopsis (Arabidopsis thaliana) Yellow Stripe-Like (YSL) family, AtYSL1 and AtYSL3. The YSL1 and YSL3 proteins are members of the oligopeptide transporter family and are predicted to be integral membrane proteins. YSL1 and YSL3 are similar to the maize (Zea mays) YS1 phytosiderophore transporter (ZmYS1) and the AtYSL2 iron (Fe)-nicotianamine transporter, and are predicted to transport metal-nicotianamine complexes into cells. YSL1 and YSL3 mRNAs are expressed in both root and shoot tissues, and both are regulated in response to the Fe status of the plant. β-Glucuronidase reporter expression, driven by YSL1 and YSL3 promoters, reveals expression patterns of the genes in roots, leaves, and flowers. Expression was highest in senescing rosette leaves and cauline leaves. Whereas the single mutants ysl1 and ysl3 had no visible phenotypes, the ysl1ysl3 double mutant exhibited Fe deficiency symptoms, such as interveinal chlorosis. Leaf Fe concentrations are decreased in the double mutant, whereas manganese, zinc, and especially copper concentrations are elevated. In seeds of double-mutant plants, the concentrations of Fe, zinc, and copper are low. Mobilization of metals from leaves during senescence is impaired in the double mutant. In addition, the double mutant has reduced fertility due to defective anther and embryo development. The proposed physiological roles for YSL1 and YSL3 are in delivery of metal micronutrients to and from vascular tissues

Spin coherence transfer in chemical transformations monitoredNMR

We demonstrate the use of micro-scale nuclear magneticresonance (NMR) for studying the transfer of spin coherence innon-equilibrium chemical processes, using spatially separated NMRencoding and detection coils. As an example, we provide the map ofchemical shift correlations for the amino acid alanine as it transitionsfrom the zwitterionic to the anionic form. Our method is unique in thesense that it allows us to track the chemical migration of encodednuclear spins during the course of chemical transformations

Miscellaneous Problems

Contains reports on eight research projects

Null Deformed Domain Wall

We study null 1/4 BPS deformations of flat domain wall solutions (NDDW) in N=2, d=5 gauged supergravity with hypermultiplets and vector multiplets coupled. These are uncharged time-dependent configurations and contain as special case, 1/2 supersymmetric flat domain walls (DW), as well as 1/2 BPS null solutions of the ungauged supergravity. Combining our analysis with the classification method initiated by Gauntlett et al., we prove that all the possible deformations of the DW have origin in the hypermultiplet sector or/and are null. Here, we classify all the null deformations: we show that they naturally organize themselves into "gauging" (v-deformation) and "non gauging" (u-deformation). They have different properties: only in presence of v-deformation is the solution supported by a time-dependent scalar potential. Furthermore we show that the number of possible deformations equals the number of matter multiplets coupled. We discuss the general procedure for constructing explicit solutions, stressing the crucial role taken by the integrability conditions of the scalars as spacetime functions. Two analytical solutions are presented. Finally, we comment on the holographic applications of the NDDW, in relation to the recently proposed time-dependent AdS/CFT.Comment: 38 pages; minor changes, references added; text revised, minor changes, final version published in JHE

Evidence for distinct coastal and offshore communities of bottlenose dolphins in the north east Atlantic.

Bottlenose dolphin stock structure in the northeast Atlantic remains poorly understood. However, fine scale photo-id data have shown that populations can comprise multiple overlapping social communities. These social communities form structural elements of bottlenose dolphin (Tursiops truncatus) [corrected] populations, reflecting specific ecological and behavioural adaptations to local habitats. We investigated the social structure of bottlenose dolphins in the waters of northwest Ireland and present evidence for distinct inshore and offshore social communities. Individuals of the inshore community had a coastal distribution restricted to waters within 3 km from shore. These animals exhibited a cohesive, fission-fusion social organisation, with repeated resightings within the research area, within a larger coastal home range. The offshore community comprised one or more distinct groups, found significantly further offshore (>4 km) than the inshore animals. In addition, dorsal fin scarring patterns differed significantly between inshore and offshore communities with individuals of the offshore community having more distinctly marked dorsal fins. Specifically, almost half of the individuals in the offshore community (48%) had characteristic stereotyped damage to the tip of the dorsal fin, rarely recorded in the inshore community (7%). We propose that this characteristic is likely due to interactions with pelagic fisheries. Social segregation and scarring differences found here indicate that the distinct communities are likely to be spatially and behaviourally segregated. Together with recent genetic evidence of distinct offshore and coastal population structures, this provides evidence for bottlenose dolphin inshore/offshore community differentiation in the northeast Atlantic. We recommend that social communities should be considered as fundamental units for the management and conservation of bottlenose dolphins and their habitat specialisations