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  1. Article ; Online: Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy

    Al-Hassan J. Dajani / Michael B. Liu / Michael A. Olaopa / Lucian Cao / Carla Valenzuela-Ripoll / Timothy J. Davis / Megan D. Poston / Elizabeth H. Smith / Jaime Contreras / Marissa Pennino / Christopher M. Waldmann / Donald B. Hoover / Jason T. Lee / Patrick Y. Jay / Ali Javaheri / Roger Slavik / Zhilin Qu / Olujimi A. Ajijola

    JCI Insight, Vol 8, Iss

    2023  Volume 22

    Abstract: Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We ... ...

    Abstract Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.
    Keywords Cardiology ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia

    Monique R. Heitmeier / Maria A. Payne / Carla Weinheimer / Attila Kovacs / Richard C. Hresko / Patrick Y. Jay / Paul W. Hruz

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Volume 10

    Abstract: Abstract GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. ...

    Abstract Abstract GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and −12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor α (PPARα) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57Bl/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Exenatide improves glucose homeostasis and prolongs survival in a murine model of dilated cardiomyopathy.

    Arpita Kalla Vyas / Kai-Chien Yang / Dennis Woo / Anatoly Tzekov / Attila Kovacs / Patrick Y Jay / Paul W Hruz

    PLoS ONE, Vol 6, Iss 2, p e

    2011  Volume 17178

    Abstract: There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that ...

    Abstract There is growing awareness of secondary insulin resistance and alterations in myocardial glucose utilization in congestive heart failure. Whether therapies that directly target these changes would be beneficial is unclear. We previously demonstrated that acute blockade of the insulin responsive facilitative glucose transporter GLUT4 precipitates acute decompensated heart failure in mice with advanced dilated cardiomyopathy. Our current objective was to determine whether pharmacologic enhancement of insulin sensitivity and myocardial glucose uptake preserves cardiac function and survival in the setting of primary heart failure.The GLP-1 agonist exenatide was administered twice daily to a murine model of dilated cardiomyopathy (TG9) starting at 56 days of life. TG9 mice develop congestive heart failure and secondary insulin resistance in a highly predictable manner with death by 12 weeks of age. Glucose homeostasis was assessed by measuring glucose tolerance at 8 and 10 weeks and tissue 2-deoxyglucose uptake at 75 days. Exenatide treatment improved glucose tolerance, myocardial GLUT4 expression and 2-deoxyglucose uptake, cardiac contractility, and survival over control vehicle-treated TG9 mice. Phosphorylation of AMP kinase and AKT was also increased in exenatide-treated animals. Total myocardial GLUT1 levels were not different between groups. Exenatide also abrogated the detrimental effect of the GLUT4 antagonist ritonavir on survival in TG9 mice.In heart failure secondary insulin resistance is maladaptive and myocardial glucose uptake is suboptimal. An incretin-based therapy, which addresses these changes, appears beneficial.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2011-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

    Schillebeeckx, Maximiliaan / Anja Schrade / Ann-Kathrin Löbs / David B. Wilson / Elisabeth Gretzinger / Franziska Thol / Marjut Pihlajoki / Markku Heikinheimo / Patrick Y. Jay / Rebecca Cochran / Robi D. Mitra / Theresa Hiller / Theresa Röhrig / Wei Yang

    Molecular and Cellular Endocrinology. 2015 Jan. 05, v. 399

    2015  

    Abstract: Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced ... ...

    Abstract Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT-PCR, in situ hybridization, and immunohistochemistry. Microarray expression profiling of whole adrenal mRNA from ovariectomized vs. intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX-induced adrenocortical tumors of the mouse. A complementary candidate gene approach identified Foxl2 as another gonadal-like marker expressed in GDX-induced neoplasms of the mouse and ferret. That both “male-specific” (Spinlw1) and “female-specific” (Foxl2) markers were identified is noteworthy and implies that the neoplasms exhibit mixed characteristics of male and female gonadal somatic cells. Genome-wide methylation analysis showed that two genes with hypomethylated promoters, Igfbp6 and Foxs1, are upregulated in GDX-induced adrenocortical neoplasms. These new genetic and epigenetic markers may prove useful for studies of steroidogenic cell development and for diagnostic testing.
    Keywords DNA methylation ; epigenetics ; females ; ferrets ; gene expression regulation ; genes ; gonads ; immunohistochemistry ; in situ hybridization ; males ; messenger RNA ; mice ; microarray technology ; neoplasms ; ovariectomy ; reverse transcriptase polymerase chain reaction ; somatic cells ; transcriptomics
    Language English
    Dates of publication 2015-0105
    Size p. 122-130.
    Publishing place Elsevier Ireland Ltd
    Document type Article
    ZDB-ID 187438-x
    ISSN 1872-8057 ; 0303-7207
    ISSN (online) 1872-8057
    ISSN 0303-7207
    DOI 10.1016/j.mce.2014.09.029
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Correction

    Bin Zhang / Jufang Chang / Ming Fu / Jie Huang / Rakesh Kashyap / Ezequiel Salavaggione / Sanjay Jain / Shashikant Kulkarni / Matthew A. Deardorff / Maria L. Giovannucci Uzielli / Dale Dorsett / David C. Beebe / Patrick Y. Jay / Robert O. Heuckeroth / Ian Krantz / Jeffrey Milbrandt

    PLoS ONE, Vol 4, Iss

    Dosage Effects of Cohesin Regulatory Factor PDS5 on Mammalian Development: Implications for Cohesinopathies.

    2009  Volume 5

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Correction

    Bin Zhang / Jufang Chang / Ming Fu / Jie Huang / Rakesh Kashyap / Ezequiel Salavaggione / Sanjay Jain / Shashikant Kulkarni / Matthew A. Deardorff / Maria L. Giovannucci Uzielli / Dale Dorsett / David C. Beebe / Patrick Y. Jay / Robert O. Heuckeroth / Ian Krantz / Jeffrey Milbrandt

    PLoS ONE, Vol 4, Iss

    Dosage Effects of Cohesin Regulatory Factor PDS5 on Mammalian Development: Implications for Cohesinopathies

    2009  Volume 5

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2009-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Dosage effects of cohesin regulatory factor PDS5 on mammalian development

    Bin Zhang / Jufang Chang / Ming Fu / Jie Huang / Rakesh Kashyap / Ezequiel Salavaggione / Sanjay Jain / Shashikant Kulkarni / Matthew A Deardorff / Maria L Giovannucci Uzielli / Dale Dorsett / David C Beebe / Patrick Y Jay / Robert O Heuckeroth / Ian Krantz / Jeffrey Milbrandt

    PLoS ONE, Vol 4, Iss 5, p e

    implications for cohesinopathies.

    2009  Volume 5232

    Abstract: Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two ... ...

    Abstract Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B(-/-) mice. While Pds5A(-/-) and Pds5B(-/-) mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A(-/-) or Pds5B(-/-) mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2009-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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