Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

Background and Purpose: Inflammation plays a key role in atherosclerosis. A protective role of angiotensin-(1-7) in vascular pathologies opened a possibility for therapeutic use of small molecule non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms of these vaso-protective effects of a Mas receptor agonist, AVE0991, remain unclear. Experimental approach: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in ApoE-/- mice, in the context of vascular inflammation and plaque stability. Key Results: AVE0991 has significant anti-atherosclerotic properties in ApoE-/- mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using descending aorta of chow fed ApoE-/- mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (pVAT) and adventitial infiltration with macrophages and T cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability as a measure of endothelial function. AVE0991 inhibited perivascular inflammation, through the reduction of chemokine expression in pVAT, as well as through direct actions on monocytes/macrophages inhibiting their activation, characterized by IL-1β, TNF-α, MCP-1 and CXCL10 and differentiation to M1 phenotype. Pre-treatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in pVAT and in THP-1 cells in vitro and anti-inflammatory effects of AVE0991 were partially Mas dependent. Conclusions & implications: Selective Mas receptor agonist AVE0991 possesses anti-atherosclerotic and anti-inflammatory properties, affecting monocyte/macrophage differentiation and recruitment to perivascular space at early stages of atherosclerosis in ApoE-/- mice

Nitric oxide modulates expression of extracellular matrix genes linked to fibrosis in kidney mesangial cells

Mesangial cells are thought to be important mediators of glomerular inflammation and fibrosis. Studies have established a direct role for nitric oxide (NO) in the regulation of gene expression in mesangial cells. Representational difference analysis was used to investigate changes in gene expression elicited by the treatment of S-nitroso-L-glutathione in rat mesangial cells. Seven upregulated and 11 downregulated genes were identified. Four out of 11 downregulated genes (connective tissue growth factor, thrombospondin-1, collagen type I all and collagen type I alpha 2) are known to be linked to inflammation and fibrosis. Results were verified across species in mesangial cells treated with a series of NO donors using Northern blot analysis, quantitative real-time PCR and protein analysis methods. Induction of endogenous NO production by cytokine stimulation also triggered regulation of the genes. One example gene, connective tissue growth factor, was studied at the promoter level. Promoter-reporter gene studies in mesangial cells demonstrated that NO acts at the transcriptional level to suppress gene expression. Our results reveal a complex role of NO in regulating gene expression in mesangial cells and suggest an antifibrotic potential for NO

Effects of interleukin-1β Inhibition on blood pressure, incident hypertension, and residual inflammatory risk

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85–1.08], P>0.2). IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension

Nox1/4 inhibition exacerbates age dependent perivascular inflammation and fibrosis in a model of spontaneous hypertension

Hypertension is associated with oxidative stress and perivascular inflammation, critical contributors to perivascular fibrosis and accelerated vascular ageing. Oxidative stress can promote vascular inflammation, creating options for potential use of NADPH oxidase inhibitors in pharmacological targeting of perivascular inflammation and its consequences. Accordingly, we characterized age-related changes in oxidative stress and immune cell infiltration in normotensive (WKY) and spontaneously hypertensive rats (SHRs). Subsequently, we used pharmacological inhibitors of Nox1 (ML171) and Nox1/Nox4 (GKT137831; 60 mg/kg), to modulate NADPH oxidase activity at the early stage of spontaneous hypertension and investigated their effects on perivascular inflammation and fibrosis. Results: Ageing was associated with a progressive increase of blood pressure as well as an elevation of the total number of leukocytes, macrophages and NK cells infiltrating perivascular adipose tissue (PVAT) in SHRs but not in WKY. At 1 month of age, when blood pressure was not yet different, only perivascular NK cells were significantly higher in SHR. Spontaneous hypertension was also accompanied by the higher perivascular T cell accumulation, although this increase was age independent. Aortic Nox1 and Nox2 mRNA expression increased with age only in SHR but not in WKY, while age-related increase of Nox4 mRNA in the vessels has been observed in both groups, it was more pronounced in SHRs. At early stage of hypertension (3-months) the most pronounced differences were observed in Nox1 and Nox4. Surprisingly, GKT137831, dual inhibitor of Nox1/4, therapy increased both blood pressure and perivascular macrophage infiltration. Mechanistically, this was linked to increased expression of proinflammatory chemokines expression (CCL2 and CCL5) in PVAT. This inflammatory response translated to increased perivascular fibrosis. This effect was likely Nox4 dependent as the Nox1 inhibitor ML171 did not affect the development of spontaneous hypertension, perivascular macrophage accumulation, chemokine expression nor adventitial collagen deposition. In summary, spontaneous hypertension promotes ageing-associated perivascular inflammation which is exacerbated by Nox4 but not Nox1 pharmacological inhibition

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements

A search for resonances decaying into a Higgs boson and a new particle X in the XH → qqbb final state with the ATLAS detector

A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb−1 of proton–proton collision data at collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle X is assumed to decay to a pair of light quarks, and the fully hadronic final state is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the resonance

Measurement of prompt photon production in sNN√=8.16 TeV p+Pb collisions with ATLAS

The inclusive production rates of isolated, prompt photons in p+Pb collisions at sNN√=8.16 TeV are studied with the ATLAS detector at the Large Hadron Collider using a dataset with an integrated luminosity of 165 nb−1 recorded in 2016. The cross-section and nuclear modification factor RpPb are measured as a function of photon transverse energy from 20 GeV to 550 GeV and in three nucleon-nucleon centre-of-mass pseudorapidity regions, (-2.83,-2.02), (-1.84,0.91), and (1.09,1.90). The cross-section and RpPb values are compared with the results of a next-to-leading-order perturbative QCD calculation, with and without nuclear parton distribution function modifications, and with expectations based on a model of the energy loss of partons prior to the hard scattering. The data disfavour a large amount of energy loss and provide new constraints on the parton densities in nuclei.We acknowledge the support of ANPCyT, Argentina; YerPhI, Ar-menia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azer-baijan; SSTC, Belarus; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; CONICYT, Chile; CAS, MOST and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS, CEA-DRF/IRFU, France; SRNSFG, Georgia; BMBF, HGF, and MPG, Germany; GSRT, Greece; RGC, Hong Kong SAR, China; ISF and Benoziyo Center, Is-rael; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; NWO, Netherlands; RCN, Norway; MNiSW and NCN, Poland; FCT, Portu-gal; MNE/IFA, Romania; MES of Russia and NRC KI, Russian Fed-eration; JINR; MESTD, Serbia; MSSR, Slovakia; ARRS and MIZŠ, Slovenia; DST/NRF, South Africa; MINECO, Spain; SRC and Wallen-berg Foundation, Sweden; SERI, SNSF and Cantons of Bern and Geneva, Switzerland; MOST, Taiwan; TAEK, Turkey; STFC, United Kingdom; DOE and NSF, United States of America. In addition, in-dividual groups and members have received support from BCKDF, Canarie, CRC and Compute Canada, Canada; COST, ERC, ERDF, Hori-zon 2020, and Marie Skłodowska-Curie Actions, European Union; Investissements d’ Avenir Labex and Idex, ANR, France; DFG and AvH Foundation, Germany; Herakleitos, Thales and Aristeia pro-grammes co-financed by EU-ESF and the Greek NSRF, Greece; BSF-NSF and GIF, Israel; CERCA Programme Generalitat de Catalunya, Spain; The Royal Society and Leverhulme Trust, United Kingdom

Search for an invisibly decaying Higgs boson or dark matter candidates produced in association with a Z boson in pp collisions at root s=13 TeV with the ATLAS detector

SCOAP

Comparison between simulated and observed LHC beam backgrounds in the ATLAS experiment at Ebeam =4 TeV

Results of dedicated Monte Carlo simulations of beam-induced background (BIB) in the ATLAS experiment at the Large Hadron Collider (LHC) are presented and compared with data recorded in 2012. During normal physics operation this background arises mainly from scattering of the 4 TeV protons on residual gas in the beam pipe. Methods of reconstructing the BIB signals in the ATLAS detector, developed and implemented in the simulation chain based on the \textscFluka Monte Carlo simulation package, are described. The interaction rates are determined from the residual gas pressure distribution in the LHC ring in order to set an absolute scale on the predicted rates of BIB so that they can be compared quantitatively with data. Through these comparisons the origins of the BIB leading to different observables in the ATLAS detectors are analysed. The level of agreement between simulation results and BIB measurements by ATLAS in 2012 demonstrates that a good understanding of the origin of BIB has been reached

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

BACKGROUND We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424.