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  • American Physiological Society  (3)
  • 1
    Online Resource
    Online Resource
    Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Cell Physiology Vol. 311, No. 2 ( 2016-08-01), p. C330-C339
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 311, No. 2 ( 2016-08-01), p. C330-C339
    Abstract: Fibroblasts, the most abundant cells in the heart, contribute to cardiac fibrosis, the substrate for the development of arrythmogenesis, and therefore are potential targets for preventing arrhythmic cardiac remodeling. A chamber-specific difference in the responsiveness of fibroblasts from the atria and ventricles toward cytokine and growth factors has been described in animal models, but it is unclear whether similar differences exist in human cardiac fibroblasts (HCFs) and whether drugs affect their proliferation differentially. Using cardiac fibroblasts from humans, differences between atrial and ventricular fibroblasts in serum-induced proliferation, DNA synthesis, cell cycle progression, cyclin gene expression, and their inhibition by simvastatin were determined. The serum-induced proliferation rate of human atrial fibroblasts was more than threefold greater than ventricular fibroblasts with faster DNA synthesis and higher mRNA levels of cyclin genes. Simvastatin predominantly decreased the rate of proliferation of atrial fibroblasts, with inhibition of cell cycle progression and an increase in the G0/G1 phase in atrial fibroblasts with a higher sensitivity toward inhibition compared with ventricular fibroblasts. The DNA synthesis and mRNA levels of cyclin A, D, and E were significantly reduced by simvastatin in atrial but not in ventricular fibroblasts. The inhibitory effect of simvastatin on atrial fibroblasts was abrogated by mevalonic acid (500 μM) that bypasses 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition. Chamber-specific differences exist in the human heart because atrial fibroblasts have a higher proliferative capacity and are more sensitive to simvastatin-mediated inhibition through HMG-CoA reductase pathway. This mechanism may be useful in selectively preventing excessive atrial fibrosis without inhibiting adaptive ventricular remodeling during cardiac injury.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00056.2016
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Aging-related increase in store-operated Ca 2+ influx in human ventricular fibroblasts
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 315, No. 1 ( 2018-07-01), p. H83-H91
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 315, No. 1 ( 2018-07-01), p. H83-H91
    Abstract: Senescence-related fibrosis contributes to cardiac dysfunction. Profibrotic processes are Ca 2+ dependent. The effect of aging on the Ca 2+ mobilization processes of human ventricular fibroblasts (hVFs) is unclear. Therefore, we tested whether aging altered intracellular Ca 2+ release and store-operated Ca 2+ entry (SOCE). Disease-free hVFs from 2- to 63-yr-old trauma victims were assessed for cytosolic Ca 2+ dynamics with fluo 3/confocal imaging. Angiotensin II or thapsigargin was used to release endoplasmic reticulum Ca 2+ in Ca 2+ -free solution; CaCl 2 (2 mM) was then added to assess SOCE, which was normalized to ionomycin-induced maximal Ca 2+ . The angiotensin II experiments were repeated after phosphoenolpyruvate pretreatment to determine the role of energy status. The expression of genes encoding SOCE-related ion channel subunits was assessed by quantitative PCR, and protein expression was assessed by immunoblot analysis. Age groups of 〈 50 and ≥50 yr were compared using unpaired t-test or regression analysis. Ca 2+ release by angiotensin II or thapsigargin was not different between the groups, but SOCE was significantly elevated in the ≥50-yr group. Regression analysis showed an age-dependent phosphoenolpyruvate-sensitive increase in SOCE of hVFs. Aging did not alter the mRNA expression of SOCE-related genes. The profibrotic phenotype of hVFs was evident by sprouty1 downregulation with age. Thus, an age-associated increase in angiotensin II- and thapsigargin-induced SOCE occurs in hVFs, independent of receptor mechanisms or alterations of mRNA expression level of SOCE-related ion channel subunits but related to the cellular bioenergetics status. Elucidation of mechanisms underlying enhanced hVF SOCE with aging may refine SOCE targets to limit aging-related progression of Ca 2+ -dependent cardiac fibrosis. NEW & NOTEWORTHY Human ventricular fibroblasts exhibit an age-related increase in store-operated Ca 2+ influx induced by angiotensin II, an endogenous vasoactive hormone, or thapsigargin, an inhibitor of endoplasmic reticulum Ca 2+ -ATPase, independent of receptor mechanisms or genes encoding store-operated Ca 2+ entry-related ion channel subunits. Selective inhibition of this augmented store-operated Ca 2+ entry could therapeutically limit aging-related cardiac fibrosis.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00588.2017
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 311, No. 1 ( 2016-07-01), p. H54-H63
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 311, No. 1 ( 2016-07-01), p. H54-H63
    Abstract: Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O 2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 ± 0.007 vs. 0.09 ± 0.006 nmol·min −1 ·citrate synthase activity −1 , P = 0.02) and II (0.11 ± 0.012 vs. 0.16 ± 0.012 nmol·min −1 ·citrate synthase activity −1 , P = 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 ± 0.027 vs. 0.12 ± 0.01 nmol·min −1 ·citrate synthase activity −1 , P = 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 ± 17 vs. 11 ± 2 arbitrary units, P = 0.03) and 4-hydroxynonenal level (77.64 ± 30.2 vs. 9.83 ± 2.83 ng·mg −1 protein, P = 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00699.2015
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
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    Online Resource
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    Availability (electronic / print)
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