83,482 research outputs found
Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy
No full textMaternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system
Successful simulation in social services: two case studies
No full textIn this paper we briefly describe two studies undertaken with Hampshire Social Services. Both involved the use of discrete-event simulation to solve a genuine problem. Based on these studies, we compare the use of simulation in healthcare with its use in social care and discuss some differences between the two application areas. Not the least of these differences is the comparative success rate in implementation of the model results
Ang-(1-7)/ MAS1 receptor axis inhibits allergic airway inflammation via blockade of Src-mediated EGFR transactivation in a murine model of asthma - Fig 6
No full textRepresentative low-magnification light photomicrographs display H&E staining (Fig 6(a)), Masson's Trichrome staining (Fig 6(b)) and PAS stain Fig 6(c)) of whole lung samples from PBS-challenged/ vehicle treated (n = 6) (PBS), OVA-challenged/ vehicle treated (n = 6) (OVA), OVA-challenged/Ang-(1–7) treated (0.3 mg/kg; n = 6) (Ang-1–7), OVA-challenged/Ang-(1–7) and A779 treated (0.3 mg/kg; n = 6 and 1mg/kg; n = 5; respectively) (Ang-1–7 + A779), OVA-challenged/dexamethasone treated (1 mg/kg; n = 6) (DEX). OVA-challenged/vehicle treated mice showed marked and significant peribronchial and perivascular inflammatory cell infiltrations (a) peribronchial and perivascular fibrosis (b) and bronchial mucus production and goblet cell hyper/metaplasia (c) compared with PBS-challenged vehicle treated mice. Treatment with Ang-(1–7) resulted in a significant reduction in the peribronchial and perivascular dark-staining inflammatory cell infiltration (a), peribronchial and perivascular fibrosis (b) and bronchial mucus production and goblet cell hyper/metaplasia (c) compared to the OVA – challenged mice and was comparable to PBS-challenged and OVA-challenged/dexamethasone treated mice. Effect of Ang-(1–7) (0.3 mg/kg) on inflammation severity score is shown in Fig 6(d). Data are expressed as mean ± SEM (n = 5–6). *P #P P < 0.05 versus time-matched Ang-(1–7)-treated ovalbumin-challenged mice.</p
Ang-(1-7)/ MAS1 receptor axis inhibits allergic airway inflammation via blockade of Src-mediated EGFR transactivation in a murine model of asthma - Fig 8
No full textEffect of Ang (1–7) treatment on (a) neutrophil and (b) eosinophil chemotaxis towards BALF taken from either vehicle- or OVA-treated mice. Treatment with Ang-(1–7) inhibited both neutrophil and eosinophil migration. Treatment with A779 inhibited the eosinophil migration. Data are expressed as mean ± SEM (n = 5–8). *P versus time-matched PBS-challenged mice. #Pversus time-matched OVA-challenged mice.</p
Testing the rotation versus merger scenario in the galaxy cluster Abell 2107
No full textWe search for global rotation of the intracluster medium in the galaxy cluster Abell 2107, where previous studies have detected rotational motion in the member galaxies with a high-significance level. By fitting the centroid of the iron Kα line complex at 6.7–6.9 keV rest frame in Chandra ACIS-I spectra, we identify the possible rotation axis with the line that maximizes the difference between the emission-weighted spectroscopic redshift measured in the two halves defined by the line itself. Then, we measure the emission-weighted redshift in linear regions parallel to the preferred rotation axis, and find a significant gradient as a function of the projected distance from the rotation axis, compatible with a rotation pattern with maximum tangential velocity vmax = 1380 ± 600 km s−1 at a radius λ0 ∼ 160 kpc. This result, if interpreted in the framework of hydrostatic equilibrium, as suggested by the regular morphology of Abell 2107, would imply a large mass correction of the order of ∆M = (6 ± 4) × 1013 M☉ at ∼160 kpc, which is incompatible with the cluster morphology itself. A more conservative interpretation may be provided by an unnoticed off-centre, head-on collision between two comparable haloes. Our analysis confirms the peculiar dynamical nature of the otherwise regular cluster Abell 2107, but is not able to resolve the rotation versus merger scenario, a science case that can be addressed by the next-generation X-ray facilities carrying X-ray bolometers on board
Serum from People with Sepsis Disrupts Endothelial Architecture and This Effect Resolves with Clinical Improvement, Correlates with Measured Ang-2, and Is Reversed by Ang-1
No full text<div><p>Ten percent FBS or 10% serum from one of two patients with sepsis was incubated with EC monolayers to assess effects on endothelial architecture. High Ang-2 serum (Patient CE4, Ang-2 = 89 ng/ml) induced thick actin stress fibers and intercellular gap formation (D–F), whereas low Ang-2 serum (CF1, Ang-2 = 8.9 ng/ml) did not (G–I). The gap-promoting effect of Patient CE4′s serum was reversed with addition of 100 ng/ml recombinant human Ang-1 (J–L) and was indistinguishable from control cells that exhibit thin actin fibers and no intercellular gaps (A–C).</p>
<p>Serum was then taken from one patient (Patient CG), drawn on hospital day 2 (Patient CG2, Ang-2 = 78 ng/ml) and hospital day 16 (Patient CG12, Ang-2 = 6.3 ng/ml), and was added at 10% to HMVEC monolayers. Again, high-Ang-2 serum (CG2) induced gap formation and thick actin stress fibers (M–O), effects not seen in the serum of the same patient at discharge (CG12) (P–R) and effects that were reversed with the addition of 100 ng/ml Ang-1 (S–U). Arrows indicate intercellular gaps.</p></div
Proliferative synergy of ANG II and EGF in porcine aortic vascular smooth muscle cells
No full text To test growth effects of angiotensin II (ANG II) in porcine vascular smooth muscle cells (VSMC) and potential ANG II synergy with epidermal growth factor (EGF), we exposed subconfluent, near-quiescent porcine aortic VSMC to ANG II, EGF, or ANG II + EGF (each 10(-9) M) in Dulbecco's modified Eagle's-Ham's F-12 medium with insulin + 0.4% fetal calf serum (FCS) selected for minimal ANG II-degrading capacity. Cell number and DNA and protein synthesis (by [3H]-thymidine and [35S]methionine incorporation, respectively) were determined serially over 1-6 days. ANG II alone induced an early 20% increase and then a plateau in cell number over the 0.4% FCS control (P < 0.01; n = 8), thus without sustained increase in proliferation rate. Yet ANG II alone did not increase fractional DNA or protein synthesis (each as cpm/10(3) cells) and, by flow cytometry, reduced S phase fraction without increase in cell size. EGF alone induced brisk DNA synthesis yet minimal cell division over days 0-4, thus late-cycle arrest. ANG II + EGF, despite no increase in fractional DNA or protein synthesis rates over EGF alone, induced significant indomethacin-resistant dose-dependent (P < 0.001) increase in cell proliferation rate over EGF alone with a median effective dose of 5 x 10(-10) M ANG II, thus proliferative synergy. We propose that 1) ANG II induces a subpopulation of cells arrested in or beyond S phase to proceed through mitosis but does not influence G1 traversal or S phase entry and 2) ANG II + EGF achieve proliferative synergy by complementary actions at sequential cell cycle loci, with EGF supporting progression from G0/G1 to S phase and ANG II inducing completion of mitosis by cells already in or beyond S phase ("late-cycle completion"). </jats:p
Cat S deficiency enhances Ang II-induced cardiac fibrosis in mouse heart.
No full text<p>(<b>A</b>) Representative Masson trichrome staining of WT and Cat S<sup>−/−</sup> hearts with saline or Ang II infusion and quantitative analysis of fibrotic areas. Immunohistochemical staining and quantification of (<b>B</b>) collagen I, (<b>C</b>) transforming growth factor (TGF)- β1 (<b>D</b>) and (<b>E</b>) α-SMA in WT and Cat S<sup>−/−</sup> hearts with saline or Ang II infusion. Bars, 50 µm. Data are mean±SEM (n = 4 per group). **P<0.01 <i>vs.</i> saline Cat S KO control; <sup>#</sup>P<0.05, <sup>##</sup>P<0.01 <i>vs.</i> Ang II-infused WT mice. <sup>§</sup>P<0.05 <i>vs.</i> saline WT control.</p
Empagliflozin treatment does not affect the hypertensive response to Ang II administration to rats but decreases oxidative stress in the arterial wall, and endothelial and cardiac dysfunction
No full textBackground Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular disease independently of glycemic control. Angiotensin II (Ang II) and H2O2 have been shown to be strong inducers of the expression of SGLT2 and 1 in endothelial cells promoting oxidative stress and endothelial dysfunction. Purpose This study examined the cardiovascular protective effect of empagliflozin (empa) in a normoglycemic experimental model of hypertension in the rat. Methods Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by sphygmomanometry, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, and the level of oxidative stress using dihydroethidium staining. Results Angiotensin II administration increased systolic blood pressure from about 130 to 180 mmHg, which was not affected by the empa treatment. The 4-week Ang II treatment did not significantly affect the systolic cardiac function (cardiac output, left ventricle ejection fraction) but impaired the diastolic function as indicated by a reduced E' and IVRT values, and an increased E/E' value. The Ang II treatment increased significantly the heart and right ventricle weight whereas the left ventricle + septum weight was slightly but not significantly increased. No such functional and structural changes were observed in the Ang II + empa treatment group. An increased immunofluorescence eNOS signal in the endothelium, and a higher level of ROS throughout the aorta wall were observed in the Ang II-treated group, both of which were significantly reduced in the empa + Ang II-treated group. In the Ang II-treated group, the high level of oxidative stress in the aorta was significantly reduced by the AT1 receptor antagonist losartan, the NADPH oxidase inhibitor VAS-2871, the eNOS inhibitor NG-nitro-L-arginine and also to a greater extent by the selective SGLT2 inhibitor empa compared to the dual SGLT1/2 inhibitor sotagliflozin. Conclusion(s) The present findings indicate that although the empa treatment did not affect the hypertensive response of rats to Ang II, the SGLT2 inhibitor prevented the deleterious impact of Ang II on the diastolic cardiac function and remodeling, and the upregulation of eNOS expression and oxidative stress in the aorta wall. Thus, these findings highlight the protective potential of empa on the cardiovascular system in a normoglycemic hypertensive experimental model.
Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH & Co KG (Biberach an der Riss, Germany
Ang-II increased PCNA in mesenteric SMC from P-467L mice.
No full textA) Western blots showing PCNA and β-Actin in cultured mesenteric SMC from S-P467L and NT mice. B) Western blots showing PCNA in response to Ang-II in mesenteric VSMC from S-P467L and NT control mice. Time (hours) after Ang-II-treatment is indicated. The molecular weight of the indicated band is based on comparison to size markers.</p
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