Cardiovascular Response to Beta-Adrenergic Blockade or Activation in 23 Inbred Mouse Strains

Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(8):e6610. DOI: 10.1371/journal.pone.0006610
Source: PubMed


We report the characterisation of 27 cardiovascular-related traits in 23 inbred mouse strains. Mice were phenotyped either in response to chronic administration of a single dose of the beta-adrenergic receptor blocker atenolol or under a low and a high dose of the beta-agonist isoproterenol and compared to baseline condition. The robustness of our data is supported by high trait heritabilities (typically H(2)>0.7) and significant correlations of trait values measured in baseline condition with independent multistrain datasets of the Mouse Phenome Database. We then focused on the drug-, dose-, and strain-specific responses to beta-stimulation and beta-blockade of a selection of traits including heart rate, systolic blood pressure, cardiac weight indices, ECG parameters and body weight. Because of the wealth of data accumulated, we applied integrative analyses such as comprehensive bi-clustering to investigate the structure of the response across the different phenotypes, strains and experimental conditions. Information extracted from these analyses is discussed in terms of novelty and biological implications. For example, we observe that traits related to ventricular weight in most strains respond only to the high dose of isoproterenol, while heart rate and atrial weight are already affected by the low dose. Finally, we observe little concordance between strain similarity based on the phenotypes and genotypic relatedness computed from genomic SNP profiles. This indicates that cardiovascular phenotypes are unlikely to segregate according to global phylogeny, but rather be governed by smaller, local differences in the genetic architecture of the various strains.

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Available from: Jacques S Beckmann, Oct 07, 2015
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    • "In contrast, FVB/N mice are relatively resistant and show delayed transition to decompensated heart failure [39]. Furthermore, a study by Berthonneche et al., 2009 [38] on cardiovascular-related phenotypes upon β-adrenergic challenge in 23 strains of mice with different genetic backgrounds, indicated compartmental and strain-specific cardiac sensitivity to isoproterenol, with atria responding at lower concentrations than ventricles in the majority of the strains. Although the biological mechanisms underlying differential sensitivities to chronic β-stimulation are not known, the authors speculated that it might reflect distinct and strain-specific distributions of atrial and ventricular β-adrenergic receptors and/or differential downstream signaling pathways. "
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    ABSTRACT: Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.
    PLoS ONE 12/2013; 8(12):e80717. DOI:10.1371/journal.pone.0080717 · 3.23 Impact Factor
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    • "See Table 2 for ‘What's New’ in MPD categories and intervention groups. Several of these new projects are important drug studies, including acetaminophen toxicity [Threadgill1, Threadgill2 (20–23)], haloperidol effects on behavior [Crowley1 (24,25)] and effects of β-adrenergic drugs on heart function [Maurer1 (26,27)] (Projects: S6; Interventions: S8). Most have associated publications, providing assurance that the study has been peer-reviewed and the data validated by experts. "
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    ABSTRACT: The Mouse Phenome Project was launched a decade ago to complement mouse genome sequencing efforts by promoting new phenotyping initiatives under standardized conditions and collecting the data in a central public database, the Mouse Phenome Database (MPD; MPD houses a wealth of strain characteristics data to facilitate the use of the laboratory mouse in translational research for human health and disease, helping alleviate problems involving experimentation in humans that cannot be done practically or ethically. Data sets are voluntarily contributed by researchers from a variety of institutions and settings, or in some cases, retrieved by MPD staff from public sources. MPD maintains a growing collection of standardized reference data that assists investigators in selecting mouse strains for research applications; houses treatment/control data for drug studies and other interventions; offers a standardized platform for discovering genotype-phenotype relationships; and provides tools for hypothesis testing. MPD improvements and updates since our last NAR report are presented, including the addition of new tools and features to facilitate navigation and data mining as well as the acquisition of new data (phenotypic, genotypic and gene expression).
    Nucleic Acids Research 11/2011; 40(Database issue):D887-94. DOI:10.1093/nar/gkr1061 · 9.11 Impact Factor
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    ABSTRACT: Fibroblast growth factor 2 (basic FGF or FGF2) has been shown to affect growth and differentiation in some tissues and to be required for cardiac hypertrophy in vivo. FGF2 has been shown in vitro to signal through the mitogen-activated protein kinase (MAPK) to affect cell survival and growth. To ascertain the role of FGF2 in cardiac hypertrophy, wildtype, Fgf2 knockout, non-transgenic, and FGF2 transgenic mice were treated with isoproterenol or saline via subcutaneous mini-osmotic pump implants to induce a hypertrophic response to β-adrenergic stimulation. Fgf2 knockout hearts are protected from isoproterenol-induced cardiac hypertrophy; whereas, FGF2 transgenic hearts show exacerbated cardiac hypertrophy as assessed by heart weight-to-body weight ratios and myocyte cross-sectional area. Echocardiography reveals significantly decreased fractional shortening in isoproterenol-treated FGF2 transgenic mice but not in Fgf2 knockout mice suggesting that FGF2 mediates the maladaptive cardiac dysfunction seen in cardiac hypertrophy induced by isoproterenol. Western blot analysis also reveals alterations in MAPK signaling in Fgf2 knockout and FGF2 transgenic hearts subjected to isoproterenol treatment, suggesting that this cascade mediates FGF2's pro-hypertrophic effect. Pharmacologic inhibition of extracellular signal-regulated kinase (ERK) signaling results in an attenuated hypertrophic response in isoproterenol-treated FGF2 transgenic mice, but this response is not seen with p38 mitogen-activated protein kinase (p38) pathway inhibition, suggesting that FGF2 activation of ERK but not p38 is necessary for FGF2's role in the mediation of cardiac hypertrophy.
    Molecular and Cellular Pharmacology 01/2010; 2(4):143-154. DOI:10.4255/mcpharmacol.10.20
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