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  • Role of activated CaMKII in abnormal calcium homeostasis and I(Na) remodeling after myocardial infarction: insights from mathematical modeling. 18639555

    Ca(2+)/calmodulin-dependent protein kinase II is a multifunctional serine/threonine kinase with diverse cardiac roles including regulation of excitation contraction, transcription, and apoptosis. Dynamic regulation of CaMKII activity occurs in cardiac disease and is linked to specific disease phenotypes through its effects on ion channels, transporters, transcription and cell death pathways. Recent mathematical models of the cardiomyocyte have incorporated limited elements of CaMKII signaling to advance our understanding of how CaMKII regulates cardiac contractility and excitability. Given the importance of CaMKII in cardiac disease, it is imperative that computer models evolve to capture the dynamic range of CaMKII activity. In this study, using mathematical modeling combined with biochemical and imaging techniques, we test the hypothesis that CaMKII signaling in the canine infarct border zone (BZ) contributes to impaired calcium homeostasis and electrical remodeling. We report that the level of CaMKII autophosphorylation is significantly increased in the BZ region. Computer simulations using an updated mathematical model of CaMKII signaling reproduce abnormal Ca(2+) transients and action potentials characteristic of the BZ. Our simulations show that CaMKII hyperactivity contributes to abnormal Ca(2+) homeostasis and reduced action potential upstroke velocity due to effects on I(Na) gating kinetics. In conclusion, we present a new mathematical tool for studying effects of CaMKII signaling on cardiac excitability and contractility over a dynamic range of kinase activities. Our experimental and theoretical findings establish abnormal CaMKII signaling as an important component of remodeling in the canine BZ.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3068

  • Calcitriol modulation of cardiac contractile performance via protein kinase C. 16815434

    Vitamin D(3) deficiency enhances cardiac contraction in experimental studies, yet paradoxically this deficiency is linked to congestive heart failure in humans. Activated vitamin D(3) (1alpha,25-dihydroxyvitamin D(3)) or calcitriol, decreases peak force and activates protein kinase C (PKC) in isolated perfused hearts. However, the direct influence of this hormone on adult cardiac myocyte contractile function is not well understood. Our aim is to investigate whether 1alpha,25-dihydroxyvitamin D(3) acutely modulates contractile function via PKC activation in adult rat cardiac myocytes. Sarcomere shortening and re-lengthening were measured in electrically stimulated myocytes isolated from adult rat hearts, and the vitamin D(3) response (10(-10) to 10(-7) M) was compared to shortening observed under basal conditions. Maximum changes in sarcomere shortening and relaxation were observed with 10(-9) M 1alpha,25-dihydroxyvitamin D(3). This dose decreased peak shortening, and accelerated contraction and relaxation rates within 5 min of administration, and changes in the Ca(2+) transient contributed to the peak shortening and relaxation effects. The PKC inhibitor, bis-indolylmaleimide (500 nM) largely blocked the acute influence of the most potent dose (10(-9) M) on contractile function. While peak shortening and shortening rate returned to baseline within 30 min, there was a sustained acceleration of relaxation that continued over 60 min. Phosphorylation of the Ca(2+) regulatory proteins, phospholamban, and cardiac troponin I correlated with the accelerated relaxation observed in response to acute application of 1alpha,25-dihydroxyvitamin D(3). Accelerated relaxation continued to be observed after chronic addition of 1alpha,25-dihydroxyvitamin D(3) (e.g. 2 days), yet this sustained increase in relaxation was not associated with increased phosphorylation of phospholamban or troponin I. These results provide evidence that 1alpha,25-dihydroxyvitamin D(3) directly modulates adult myocyte contractile function, and protein kinase C plays an important signaling role in the acute response. Phosphorylation of key Ca(2+) regulatory proteins by this kinase contributes to the enhanced relaxation observed in response to acute, but not chronic calcitriol.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB1691
    Nombre del producto:
    Anti-Troponin I Antibody, a.a. 186-192, clone C5

  • Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK. 24265116

    The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H(2)O(2) generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H(2)O(2) generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Complete restoration of multiple dystrophin isoforms in genetically corrected Duchenne muscular dystrophy patient-derived cardiomyocytes. 26015941

    Duchenne muscular dystrophy (DMD)-associated cardiac diseases are emerging as a major cause of morbidity and mortality in DMD patients, and many therapies for treatment of skeletal muscle failed to improve cardiac function. The reprogramming of patients' somatic cells into pluripotent stem cells, combined with technologies for correcting the genetic defect, possesses great potential for the development of new treatments for genetic diseases. In this study, we obtained human cardiomyocytes from DMD patient-derived, induced pluripotent stem cells genetically corrected with a human artificial chromosome carrying the whole dystrophin genomic sequence. Stimulation by cytokines was combined with cell culturing on hydrogel with physiological stiffness, allowing an adhesion-dependent maturation and a proper dystrophin expression. The obtained cardiomyocytes showed remarkable sarcomeric organization of cardiac troponin T and α-actinin, expressed cardiac-specific markers, and displayed electrically induced calcium transients lasting less than 1 second. We demonstrated that the human artificial chromosome carrying the whole dystrophin genomic sequence is stably maintained throughout the cardiac differentiation process and that multiple promoters of the dystrophin gene are properly activated, driving expression of different isoforms. These dystrophic cardiomyocytes can be a valuable source for in vitro modeling of DMD-associated cardiac disease. Furthermore, the derivation of genetically corrected, patient-specific cardiomyocytes represents a step toward the development of innovative cell and gene therapy approaches for DMD.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3067
    Nombre del producto:
    Anti-Connexin 43 Antibody, clone 4E6.2

  • Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy. 26110816

    Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization.In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart.These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy.
    Tipo de documento:
    Referencia
    Referencia del producto:
    16-283

  • Role of GATA binding protein 4 (GATA4) in the regulation of tooth development via GNAI3. 28484278

    Transcription factor GATA4 regulates cardiac and osteoblast differentiation. However, its role in tooth development is not clear. Therefore, we generated Wnt1-Cre;GATA4 fl/fl mice, with conditional inactivation of the GATA4 gene in the dental papilla mesenchymal cells. Phenotypic analysis showed short root deformity along with reduced expressions of odonto/osteogenic markers. Proliferation (but not apoptosis) of cells around the apical area of the root was attenuated. In vitro, we knocked down GATA4 expression in stem cells of dental apical papilla (SCAPs). Proliferation, migration and odonto/osteogenic differentiation of SCAPs were affected in the shGATA4 group. Overexpression of GATA4 in SCAPs increased mineralization. Based on our previous iTRAQ results, guanine nucleotide binding proteins 3 (GNAI3) is one of the distinct proteins after GATA4 deletion. G protein signaling is involved in bone development, remodeling, and disease. In this study, both GATA4 deletion in the mouse root and knock-down in human SCAPs decreased the expression of GNAI3. Dual-luciferase and ChIP assay confirmed the direct binding of GATA4 to the GNAI3 promoter, both in vitro and in vivo. GNAI3 knock-down significantly decreased the odonto/osteogenic differentiation ability of SCAPs. We thus establish the role of GATA4 as a novel regulator of root development and elucidate its downstream molecular events.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-371
    Nombre del producto:
    EZ-ChIP™

  • Effect of weight loss and exercise therapy on bone metabolism and mass in obese older adults: a one-year randomized controlled trial. 18364384

    BACKGROUND: Although weight loss and exercise ameliorates frailty and improves cardiac risk factors in obese older adults, the long-term effect of lifestyle intervention on bone metabolism and mass is unknown. OBJECTIVE: The objective was to evaluate the effects of diet-induced weight loss in conjunction with exercise on bone metabolism and mass in obese older adults. DESIGN AND SETTING: We conducted a one-year randomized, controlled clinical trial in a university-based research center. PARTICIPANTS: Twenty-seven frail, obese (body mass index = 39 +/- 5 kg/m(2)), older (age 70 +/- 5 yr) adults participated in the study. Intervention: Participants were randomly assigned to diet and exercise (treatment group; n = 17) or no therapy (control group; n = 10). OUTCOME MEASURES: Body weight decreased in the treatment group but not in the control group (-10 +/- 2 vs. +1 +/- 1%, P 0.001). Compared with the control group, the treatment group had greater changes in bone mass, bone markers, and hormones, including 1) bone mineral density (BMD) in total hip (0.1 +/- 2.1 vs. -2.4 +/- 2.5%), trochanter (0.2 +/- 3.3 vs. -3.3 +/- 3.1%), and intertrochanter (0.3 +/- 2.7 vs. -2.7 +/- .3.0%); 2) C-terminal telopeptide (12 +/- 35 vs. 101 +/- 79%) and osteocalcin (-5 +/- 15 vs. 66 +/- 61%); and 3) leptin (2 +/- 12 vs. -30 +/- 25%) and estradiol (0.1 +/- 14% vs. -14 +/- 21%) (all P 0.05). Changes in weight (r = 0.55), bone markers (r = -0.54), and leptin (r = 0.61) correlated with changes in hip BMD (all P 0.05). CONCLUSION: Weight loss, even when combined with exercise, decreases hip BMD in obese older adults. It is not known whether the beneficial effects of weight loss and exercise on physical function lower the overall risk of falls and fractures, despite the decline in hip BMD.
    Tipo de documento:
    Referencia
    Referencia del producto:
    HL-81K
    Nombre del producto:
    Human Leptin RIA

  • The alternative carboxyl termini of avian cardiac and brain sarcoplasmic reticulum/endoplasmic reticulum Ca(2+)-ATPases are on opposite sides of the membrane. 1533629

    The sarcoplasmic/endoplasmic reticulum slow-twitch or cardiac Ca(2+)-ATPase (SERCA2) is expressed as two forms (SERCA2a and SERCA2b) which vary at their extreme carboxyl termini. SERCA2a and SERCA2b are derived from alternatively spliced primary transcripts of the same gene. These two alternative carboxyl termini are highly conserved in mammals (Eggermont, J. A., Wuytack, F., De Jaegere, S., Nelles, L., and Casteels, R. (1989) Biochem. J. 260, 757-761; Lytton, J., and MacLennan, D. H. (1988) J. Biol. Chem. 263, 15024-15031) and birds (Campbell, A. M., Kessler, P. D., Sagara, Y., Inesi, G., and Fambrough, D. M. (1991) J. Biol. Chem. 266, 16050-16055). The topology of SERCA2a is believed to be identical to the fast-twitch Ca(2+)-ATPase (SERCA1) with 10 membrane-spanning domains. Based on hydropathy analysis, the extended carboxyl terminus of SERCA2b is predicted to span the endoplasmic reticulum (ER) membrane an additional (i.e. 11th) time. We have added the human c-myc epitope, a 10-amino acid sequence recognized by monoclonal antibody 9E10, onto the carboxyl termini of SERCA2a and SERCA2b to test whether or not their carboxyl termini are on the same side of the ER membrane. The added epitopes do not appear to disrupt topology as judged from unaltered Ca2+ transport. Immunocytochemical studies demonstrate that SERCA2a and SERCA2b have their carboxyl termini on opposite sides of the ER membrane; SERCA2a's is in the cytosol and SERCA2b's is in the ER lumen.
    Tipo de documento:
    Referencia
    Referencia del producto:
    CBL430

  • RGD-containing peptides activate S6K1 through beta3 integrin in adult cardiac muscle cells. 12909616

    The enzyme p70S6 kinase (S6K1) is critical for cell growth, and we have reported its activation during cardiac hypertrophy. Because cardiac hypertrophy also involves integrin activation, we analyzed whether integrins could contribute to S6K1 activation. Using adult feline cardiomyocytes, here we report that integrin-interacting Arg-Gly-Asp (RGD) peptides activate S6K1 as observed by band shifting, kinase activity and phosphorylation at Thr-389 and Thr-421/Ser-424 of S6K1, and S6 protein phosphorylation. Perturbation of specific integrin function with blocking antibodies and by overexpressing the beta1A cytoplasmic tail revealed that beta3 but not beta1 integrin mediates the RGD-induced S6K1 activation. This activation is focal adhesion complex-independent and is accompanied by the activation of extracellular signal-regulated kinases 1/2 (ERK) and mammalian target of rapamycin (mTOR). Studies using specific inhibitors and dominant negative c-Raf expression in cardiomyocytes indicate that the S6K1 activation involves mTOR, MEK/ERK, and phosphatidylinositol 3-kinase pathways and is independent of protein kinase C and c-Raf. Finally, addition of fluorescent-labeled RGD peptide to cardiomyocytes exhibits its internalization and localization to the endocytic vesicles, and pretreatment of cardiomyocytes with endocytic inhibitors reduced the S6K1 activation. These data suggest that RGD interaction with beta3 integrin and its subsequent endocytosis trigger specific signaling pathway(s) for S6K1 activation in cardiomyocytes and that this process may contribute to hypertrophic growth and remodeling of myocardium.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Cardiac dysfunction induced by experimental myocardial infarction impairs the host defense response to bacterial infection in mice because of reduced phagocytosis of Kupf ... 20138636

    OBJECTIVE: This study was undertaken to investigate the effects of cardiac dysfunction induced by experimental myocardial infarction on the host defense response to bacterial infection and the role of Kupffer cells in mediating this response. METHODS: Myocardial infarction was induced in C57BL/6 mice by ligation of the left anterior descending coronary artery. Mice were challenged with Escherichia coli intravenously 1, 5, and 14 days after myocardial infarction or sham operation. Thereafter, the cytokine production and the function of their Kupffer cells were assessed. RESULTS: Mice with myocardial infarction showed remarkable cardiac dysfunction and had a significantly lower survival than sham mice after bacterial challenge at 5 days after surgery; bacterial challenge at 1 or 14 days after surgery resulted in no difference in survival between myocardial infarction and sham mice. The phagocytic activity of Kupffer cells, assessed by fluorescein isothiocyanate microspheres, remarkably decreased in mice with myocardial infarction 5 days after surgery. Serum peaks of tumor necrosis factor and interferon-gamma after bacterial challenge were also suppressed in mice with myocardial infarction at 5 days. Production of these cytokines and immunoglobulin-M from liver mononuclear cells was also impaired in mice with myocardial infarction. Enhancement of the phagocytic activity of Kupffer cells by C-reactive protein significantly improved survival after infection in mice with myocardial infarction, although neither interleukin-18 nor immunoglobulin-M treatment improved survival. CONCLUSION: Cardiac dysfunction induced by myocardial infarction renders mice susceptible to bacterial infection and increases mortality because of a reduced ability of Kupffer cells to clear infectious bacteria. C-reactive protein-enhanced phagocytic activity of Kupffer cells may improve the poor prognosis after bacterial infection in mice with myocardial infarction. Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
    Tipo de documento:
    Referencia
    Referencia del producto:
    PP50
    Nombre del producto:
    IgM, Mouse