Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart.

AIMS: Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart. METHODS AND RESULTS: In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis. CONCLUSIONS: Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasis

Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart

Aims Notch1 signalling in the heart is mainly activated via expression of Jagged1 on the surface of cardiomyocytes. Notch controls cardiomyocyte proliferation and differentiation in the developing heart and regulates cardiac remodelling in the stressed adult heart. Besides canonical Notch receptor activation in signal-receiving cells, Notch ligands can also activate Notch receptor-independent responses in signal-sending cells via release of their intracellular domain. We evaluated therefore the importance of Jagged1 (J1) intracellular domain (ICD)-mediated pathways in the postnatal heart. Methods and results In cardiomyocytes, Jagged1 releases J1ICD, which then translocates into the nucleus and down-regulates Notch transcriptional activity. To study the importance of J1ICD in cardiac homeostasis, we generated transgenic mice expressing a tamoxifen-inducible form of J1ICD, specifically in cardiomyocytes. Using this model, we demonstrate that J1ICD-mediated Notch inhibition diminishes proliferation in the neonatal cardiomyocyte population and promotes maturation. In the neonatal heart, a response via Wnt and Akt pathway activation is elicited as an attempt to compensate for the deficit in cardiomyocyte number resulting from J1ICD activation. In the stressed adult heart, J1ICD activation results in a dramatic reduction of the number of Notch signalling cardiomyocytes, blunts the hypertrophic response, and reduces the number of apoptotic cardiomyocytes. Consistently, this occurs concomitantly with a significant down-regulation of the phosphorylation of the Akt effectors ribosomal S6 protein (S6) and eukaryotic initiation factor 4E binding protein1 (4EBP1) controlling protein synthesis. Conclusions Altogether, these data demonstrate the importance of J1ICD in the modulation of physiological and pathological hypertrophy, and reveal the existence of a novel pathway regulating cardiac homeostasi

The Notch pathway controls fibrotic and regenerative repair in the adult heart.

AIMS: In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling. METHODS AND RESULTS: We generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells. CONCLUSIONS: We conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cells

The Notch pathway controls fibrotic and regenerative repair in the adult heart

Aims In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling. Methods and results We generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells. Conclusions We conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cell

Red cell distribution width and mortality in acute heart failure patients with preserved and reduced ejection fraction.

Elevated red blood cell distribution width (RDW) is a valid predictor of outcome in acute heart failure (AHF). It is unknown whether elevated RDW remains predictive in AHF patients with either preserved left ventricular ejection fraction (LVEF) ≥50% or reduced LVEF (<50%). Prospective local registry including 402 consecutive hospitalized AHF patients without acute coronary syndrome or need of intensive care. The primary outcome was all-cause mortality (ACM) at 1 year after admission. Demographic and clinical data derive from admission, echocardiographic examinations (n = 269; 67%) from hospitalization. The Cox proportional hazard model including all patients (P < 0.001) was adjusted for age, gender, and RDW quartiles. Independent predictors of 1-year ACM were cardiogenic shock (HR 2.86; CI: 1.3-6.4), male sex (HR 1.9; CI: 1.2-2.9), high RDW quartile (HR 1.66; CI: 1.02-2.8), chronic HF (HR 1.61; CI: 1.05-2.5), valvular heart disease (HR 1.61; CI: 1.09-2.4), increased diastolic blood pressure (HR 1.02 per mmHg; CI: 1.01-1.03), increasing age (HR 1.04 by year; CI: 1.02-1.07), platelet count (HR 1.002 per G/l; CI: 1.0-1.004), systolic blood pressure (HR 0.99 per mmHg; CI: 0.98-0.99), and weight (HR 0.98 per kg; CI: 0.97-0.99). A total of 114 patients (28.4%) died within the first year; ACM of all patients increased with quartiles of rising RDW (χ(2) 18; P < 0.001). ACM was not different between RDW quartiles of patients with reduced LVEF (n = 153; χ(2) 6.6; P = 0.084). In AHF with LVEF ≥50% the probability of ACM increased with rising RDW (n = 116; χ(2) 9.9; P = 0.0195). High RDW is associated with increased ACM in AHF patients with preserved but not with reduced LVEF in this study population

XANES evidence for sulphur speciation in Mn-, Ni- and W-bearing silicate melts

Author Posting. © Elsevier B.V., 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 73 (2009): 6847-6867, doi:10.1016/j.gca.2009.08.013.S K edge XANES and Mn, W and Ni XANES and EXAFS spectra of silicate glasses synthesised at 1400° C and 1 bar with compositions in the CaO-MgO-Al2O3-SiO2-S plus MnO, NiO, or WO3 systems were used to investigate sulphur speciation in silicate glasses. S K-edge spectra comprised a composite peak with an edge between 2470 and 2471.4 eV, which was attributed to S2-, and a peak of variable height with an edge at 2480.2 to 2480.8 eV, which is consistent with the presence of S6+. The latter peak was attributed to sample oxidation during sample storage. W-rich samples produced an additional lower energy peak at 2469.8 eV that is tentatively attributed to the existence of S 3p orbitals hybridised with the W 5d states. Deconvolution of the composite peak reveals that the composite peak for Mn-bearing samples fits well to a model that combines three Lorentzians at 2473.1, 2474.9 and 2476.2 eV with an arctan edge step. The composite peak for W-bearing samples fits well to the same combination plus an additional Lorentzian at 2469.8 eV. The ratio of the proportions of the signal accounted for by peaks at 2473.1eV and 2476.2eV correlates with Mn:Ca molar ratios, but not with W:Ca ratios. Spectra from Ni-bearing samples were qualitatively similar but S levels were too low to allow robust quantification of peak components. Some part of the signal accounted for by the 2473.1 eV peak was therefore taken to record the formation of Mn-S melt species, while the 2469.8 peak is interpreted to record the formation of W-S melt species. The 2474.9 eV and 2476.2 eV peaks were taken to be dominated by Ca-S and Mg-S interactions. However, a 1:1 relationship between peak components and specific energy transitions is not proposed. This interpretation is consistent with known features of the lower parts of the conduction band in monosulphide minerals and indicates a similarity between sulphur species in the melts and the monosulphides. S XANES spectra cannot be reproduced by a combination of the spectra of the component element monosulphides. Mn-, W- and Ni- XANES and EXAFS for synthetic glasses without sulphide exsolution did not show any sensitivity to the presence of sulphur, which is unsurprising as S:O ratios were sufficiently low that metals would be mostly co-ordinated by O. Mn EXAFS spectra were consistent with divalent Mn in 5 co-ordinated Mn-O melt species. W spectra were consistent with tetrahedrally co-ordinated hexavalent W, most likely in scheelite-like melt species, and Ni spectra were consistent with [4] co-ordinated divalent Ni. These results indicate lower coordinations for bothWand Ni than those inferred by some previous workers. Cation coordination may reflect the proportion of non-bridging oxygens, which is lower in the Ca-rich and Al-poor samples investigated here than for previous studies.This work was performed with 814 support from the Australian Synchrotron Research Program (ASRP), which is funded by the 815 Commonwealth of Australia under the Major National Research Facilities Program

Mineralogical, geochemical, and isotopic characteristics of the ejecta from the 5 April 2003 paroxysm at Stromboli, Itlay: Inferences on the Preeruptive Magma Dynamics

The 5 April 2003 explosive eruption at Stromboli emplaced typical basaltic scoria, pumice, and lithic blocks. This paper reports a detailed set of mineralogical, geochemical, and isotopic data on the juvenile ejecta and fresh subvolcanic blocks, including micro-Sr isotope analyses and major and dissolved volatile element contents in olivine-hosted melt inclusions. The juvenile ejecta have compositions similar to those of their analogs from previous paroxysms; the 2003 pumice, however, does not contain stable high-MgO olivine, usually typical of large-scale paroxysms and has lower compatible element contents. Texture, composition, and Sr isotope disequilibrium of crystals in pumice indicate that most of them are inherited from the shallow crystal-rich magma and/or crystal mush. The most primitive magma is recorded as rare melt inclusion in olivine Fo85–86. It has a typical S/Cl (1.1) and a total volatile content of 3.1 wt % from which the total fluid pressure was evaluated ≥240 MPa. Hence, moderate pressure conditions can be envisaged for the mechanism triggering the April 2003 paroxysm. The subvolcanic blocks are shoshonitic basalts with 45–50 vol % of phenocrysts (plagioclase + clinopyroxene + olivine). The late-stage crystallization of the crystal-rich magma lead to the formation of Na-sanidine with plagioclase An60–25 + olivine Fo68–49 + Timagnetite ± apatite ± phlogopite ± ilmenite assemblage. Mineralogy, chemistry, and Sr–Nd isotopic signatures of the subvolcanic blocks indicate they represent the slowly cooled equivalents of batches of crystal-rich basaltic magma stored in the uppermost subvolcanic feeding system. Cooling might be facilitated by short breaks in the summit crater activity

Insight into volatile behavior at Nyamuragira volcano (D.R. Congo, Africa) through olivine-hosted melt inclusions

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 12 (2011): Q0AB11, doi:10.1029/2011GC003699.We present new olivine-hosted melt inclusion volatile (H2O, CO2, S, Cl, F) and major element data from five historic eruptions of Nyamuragira volcano (1912, 1938, 1948, 1986, 2006). Host-olivine Mg#'s range from 71 to 84, with the exception of the 1912 sample (Mg# = 90). Inclusion compositions extend from alkali basalts to basanite-tephrites. Our results indicate inclusion entrapment over depths ranging from 3 to 5 km, which agree with independent estimates of magma storage depths (3–7 km) based on geophysical methods. Melt compositions derived from the 1986 and 2006 Nyamuragira tephra samples best represent pre-eruptive volatile compositions because these samples contain naturally glassy inclusions that underwent less post-entrapment modification than crystallized inclusions. Volatile concentrations of the 1986 and 2006 samples are as follows: H2O ranged from 0.6 to 1.4 wt %, CO2 from 350 to 1900 ppm, S from 1300 to 2400 ppm, Cl from 720 to 990 ppm, and F from 1500 to 2200 ppm. Based on FeOT and S data, we suggest that Nyamuragira magmas have higher fO2 (>NNO) than MORB. We estimate the total amount of sulfur dioxide (SO2) released from the 1986 (0.04 Mt) and 2006 (0.06 Mt) Nyamuragira eruptions using the petrologic method, whereby S contents in melt inclusions are scaled to erupted lava volumes. These amounts are significantly less than satellite-based SO2 emissions for the same eruptions (1986 = ∼1 Mt; 2006 = ∼2 Mt). Potential explanations for this observation are: (1) accumulation of a vapor phase within the magmatic system that is only released during eruptions, and/or (2) syn-eruptive gas release from unerupted magma.Funding for this work was provided by NSF (grant EAR 0910795 (to SAC) and grant EAR 0646694 (to AMS)), as well as the National Geographic Society (grant 7698-04 (to SAC))