767 research outputs found

    Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1s/sα2s/s Mouse Model of High Affinity for Cardiotonic Steroids

    No full text
    The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1r/rα2s/s mouse failed to do so in the α1s/sα2s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions

    Ubiquitous and cell type-specific transcriptomic changes triggered by dissipation of monovalent cation gradients in rodent cells: Physiological and pathophysiological implications

    No full text
    Elevation of [Na+]i/[K+]i-ratio is considered as one of the major signals triggering transcriptomic changes in various cells types. In this study, we identified ubiquitous and cell type-specific Na+,K+ -sensitive genes by comparative analysis of transcriptomic changes in ouabain-treated rat aorta smooth muscle cells and rat aorta endothelial cells (RASMC and RAEC, respectively), rat cerebellar granule cells (RCGC), and mouse C2C12 myoblasts. Exposure of the cells to ouabain increased intracellular Na+ content by ~ 14, 8, 7, and 6-fold and resulted in appearance of 7577, 2698, 2120, and 1146 differentially expressed transcripts in RAEC, RASMC, C2C12, and RCGC, respectively. Eighty-three genes were found as the intersection of the four sets of identified transcripts corresponding to each cell type and are classified as ubiquitous. Among the 10 top upregulated ubiquitous transcripts are the following: Dusp6, Plk3, Trib1, Ccl7, Mafk, Atf3, Ptgs2, Cxcl1, Spry4, and Coq10b. Unique transcripts whose expression is cell-specific include 4897, 1523, 789, and 494 transcripts for RAEC, RASMC, C2C12, and RCGC, respectively. The role of gene expression and signal pathways induced by dissipation of transmembrane gradient of monovalent cations in the development of various diseases is discussed with special attention to cardiovascular and pulmonary illnesses

    Control of lung myofibroblast transformation by monovalent ion transporters

    No full text
    Myofibroblast differentiation is a critical process in the pathogenesis of tissue fibrosis. We focus our mini-review on recent data showing an implication of monovalent ion transporters in fibroblast to myofibroblast transformation of human lung fibroblasts (HLF). In cultured HLF, cardiotonic steroids (CTS) known as potent inhibitors of Na+,K+-ATPase suppress myofibroblast differentiation in parallel with up- and down-regulated expression of cyclooxygenase-2 (COX-2) and TGF-β receptor subunit TGFBR2, respectively. K+-free medium mimics antifibrotic action of CTS indicating a key role of elevated intracellular [Na+]i/[K+]i ratio. Augmented expression of COX-2 is abolished by inhibition of Na+/Ca2+ exchanger. Side-by-side with CTS acting via elevation of the [Na+]i/[K+]i ratio fibroblast to myofibroblast transformation is also suppressed by potent inhibitors of Ca2+-activated chloride channels tannic acid and K+,Cl- cotransporter DIOA. The relative impact of [Formula: see text] -mediated and -independent signaling triggered by elevated [Na+]i/[K+]i ratio and altered intracellular anion handling in transcriptomic changes involved in myofibroblast differentiation should be examined further

    The CLN3 gene and protein: What we know

    No full text
    One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans

    Analysis of the Fee Structure and Expense Ratios of U.S. Equity Mutual Funds

    Get PDF
    3rd place in the Business Solutions in the Global Economy category at the Denman ForumA plethora of research exists showing the relationship between a mutual fund's performance, in the form of its percentage return to investors, and a fund's expense ratio. Existing research, by Hooks (1996), Haslem, Baker, and Smith (2008), and Bello and Frank (2010), show across different samples and controls that funds with higher than average expenses under-perform compared to those with a lower ratio. With this being the case, how do mutual funds justify having a higher than average expense ratio and what are the actual factors of a fund that determine this ratio? This is a major gap in mutual fund research and although some findings do exist on the determinants of these expenses, this paper hopes to add to those findings through analysis of additional variables and controls. To do this, data was collected via the independent mutual fund database Morningstar. A screening was used to control the data set so that the results of this research would be most applicable to casual investors who are most susceptible to high expense ratios. From this screening both a year to date cross sectional set of data and a time series dataset of annual data from 2013 to 2017. A regression analysis was conducted on the cross-sectional data set and results show that both the year to date absolute return percentile and the rank percentile of the funds are both significant in determining the expense ratio. Four multiple-regression models adapted from previous research by Ferris and Chance (1987) were used to come up with results from the time-series data set. These models resulted in coefficients of determination between 50%-60%, with the size of the fund, additional load fees, and the use of a 12-b1 plan being the most significant variables.No embargoAcademic Major: Financ

    K+ and Rb+ Affinities of the Na,K-ATPase α1 and α2 Isozymes: An Application of ICP-MS for Quantification of Na+ Pump Kinetics in Myofibers

    No full text
    The potassium affinities of Na,K-ATPase isozymes are important determinants of their physiological roles in skeletal muscle. This study measured the apparent K+ and Rb+ affinities of the Na,K-ATPase α1 and α2 isozymes in intact, dissociated myofibers obtained from WT and genetically altered mice (α1S/Sα2R/R and skα2−/−). It also validates a new method to quantify cations in intact, dissociated myofibers, using inductively coupled plasma mass spectrometry (ICP-MS). Our findings were that: (1) The extracellular substrate sites of Na,K-ATPase bind Rb+ and K+ with comparable apparent affinities; however; turnover rate is reduced when Rb+ is the transported ion; (2) The rate of Rb+ uptake by the Na,K-ATPase is not constant but declines with a half-time of approximately 1.5 min; (3) The apparent K+ affinity of the α2 isozymes for K+ is significantly lower than α1. When measured in intact fibers of WT and α1S/Sα2R/R mice in the presence of 10 µM ouabain; the K1/2,K of α1 and α2 isozymes are 1.3 and 4 mM, respectively. Collectively, these results validate the single fiber model for studies of Na,K-ATPase transport and kinetic constants, and they imply the existence of mechanisms that dynamically limit pump activity during periods of active transport

    Characterisation of Na/K-ATPase, its isoforms, and the inotropic response to ouabain in isolated failing human hearts

    Get PDF
    Objective: The aim was to determine whether failing human hearts have increased sensitivity to the inotropic and toxic effects of ouabain, and to examine alterations in Na/K-ATPase that might explain the observed higher ouabain sensitivity. Methods: For contractility studies, a total of 57 trabeculae were isolated from two non- failing (death from head injury) and 10 terminally failing, explanted human hearts. After the experiment, each trabecula was inspected under the light microscope for morphological alterations consistent with heart failure. Samples for biochemical and molecular studies were obtained from five non-failing and 13 failing hearts. Total Na/K-ATPase was measured in desoxycholate treated homogenates and expressed per unit of tissue wet or dry weight, DNA, protein, or myosin. Interference from residual bound digoxin due to previous therapy was excluded. The expression of the three α isoforms was studied at both the mRNA level using northern blots and the protein level by analysis of dissociation kinetics of the [3H]ouabain-enzyme complex. Results: Trabeculae showing morphological alterations and decreased contractility were sensitive to lower concentrations of ouabain (3-100 nM) than control trabeculae (100-1000 nM); the inotropic EC50 and the minimum toxic concentration were both reduced. [3H]Ouabain binding was significantly lower (p≪0.001) in failing than in non-failing hearts, at 293(SD 74) v 507(48) pmol·g−1 wet weight. No significant change was observed in maximum ATPase turnover rate, or in sensitivities to Na+, K+, vanadate, and dihydro-ouabain. All three α isoforms were expressed at the mRNA level in both normal and failing hearts. Conclusions: This study shows conclusively, for the first time, that failing human hearts are more sensitive to ouabain. This may be at least partly due to a mean reduction of 42% (95% confidence interval, 26 to 56%) in the concentration of Na/K-ATPase (decrease in Na,K pump reserve), but not to an alteration in its catalytic properties or in its isoform composition. Cardiovascular Research 1993;27:2229-223

    Structural changes and financial frictions in the monetary transmission mechanism : GMM, VAR and Bayesian DSGE approaches

    Get PDF
    This thesis focuses on five independent but integrated current topics in macroeconomics and finance. It aims to achieve six objectives: first, it evaluates the UK monetary policy rules and determines if monetary policy rule should be different in a financial crisis and recession regimes. Second, it investigates the MTM and the dynamics of the channels before and after the GFC. Third, it explores the role of credit supply shocks and addresses if the issue of credit supply shocks has a plausible macroeconomic effects in the UK economy. Fourth, it addresses the issue of structural changes and determines the degree of significant changes assuming that MSBs exist. Specifically, the study examines the robustness of the Augmented Dickey-Fuller (ADF) and the ZA one break unit root tests to the presence of endogenously determined multiple structural breaks. Fifth, it studies credit supply shocks to determine how monetary policy and credit shocks differ during the pre and post-IT regimes. Sixth, it explores the role of MP and determines whether financial frictions that accounts for price and financial stability will have more plausible control of the economy than being limited to price stability. The empirical investigation employs a GMM, VAR and estimates Bayesian DSGE models for the UK data from 1955 to 2014. The GMM simulation analysis confirmed that the UK monetary policy is more of a forward-looking Taylor type and a hybrid Taylor-McCallum MP rules RFs with a mixture of conventional and unconventional policy frameworks in the post-Global Financial Crisis (GFC). The structural break analysis showed that the financial and monetary sectors have more persistent shocks than the macroeconomic sector. Using the MSB approach, the study identified four major structural breaks in the UK economic structure from 1960 to 2014 and showed that the ZA method does not improve the traditional ADF method. The VAR and Bayesian DSGE analyses revealed that the UK MTM has changed in the post-GFC. The empirical analysis, based on the Bayesian likelihood DSGE model, revealed that the traditional view of the interest rate channel has now been replaced by the credit channel. The specified VAR and VEC models identified the bank-lending channel as a major credit channel than the balance sheet channel. The overidentified Augmented SVAR (A-SVAR) model characterised credit supply volatilities as aggregate supply shocks that moves price and output in opposite direction. The study also investigated the prudence of monetary policy alone and monetary policy with a financial component. The DSGE model with financial frictions represented the data well and showed that the role of investment has reduced significantly in the run up to the GFC and gradually replaced by the Spread shock. Spread shocks constituted about 14% of output decline as compared with 3.5% decline due to investment shocks. Although economic theory strongly advocates the self-balancing mechanism of the financial sector, the evidence found in this study proved otherwise. The financial and monetary systems are two integral sides of the same coin
    corecore