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Role of the ubiquitin-proteasome system in the pathogenesis of cardiac hypertrophy and aging

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  • معلومة اضافية
    • الموضوع:
      2015
    • Collection:
      Heidelberg University: HeiDok
    • الموضوع:
      500; 570
    • نبذة مختصرة :
      Cardiovascular disease causes the highest morbidity and mortality worldwide. Moreover, the prevalence of cardiac hypertrophy and failure dramatically increases with aging, most notably in women. In this context, impairment of the ubiquitin-proteasome system (UPS) is supposed to be a pivotal element in the reinforcement of aging. Moreover, an involvement of the UPS, which accounts for the preservation of cardiomyocyte structure and function by the targeted degradation of structural, functional as well as signaling proteins, in the development of cardiac hypertrophy has been suggested. However, the number of systematic studies with regard to mechanisms underlying proteasome regulation in the heart and their role in cardiac remodeling, especially in the aging heart, is currently limited. Ongoing studies in our group reveal that cardiac hypertrophy due to continuous β-adrenergic stimulation in the mouse is exaggerated by knockout of the proteasome subunit β1i. The present study therefore addresses the question whether it is the absence of β1i incorporation into active cardiac proteasome complexes or its deficiency per se, which augments cardiac hypertrophy in β1i deficient mice upon treatment with isoprenaline. Reintroduction of β1i into cardiac proteasome complexes of β1i deficient mice by way of cardiac specific (serotype 9) adeno associated viral gene transfer resulted in reduced hypertrophy development, comparable to the level in isoprenaline-treated wild type mice, and prevention of a manifest systolic and diastolic dysfunction. Presumably, the augmented hypertrophy development in the isoprenaline treated β1i deficient mice is not related to a disturbance of the sarcomeric structure or a dysregulated degradation of contractile proteins. However, reassembly of β1i into active cardiac proteasome complexes seems to be associated with higher intracellular troponin I levels compared to the control group, which may contribute to the maintenance of cardiac function. In contrast to previous studies, marked alterations ...
    • File Description:
      application/pdf
    • Relation:
      https://archiv.ub.uni-heidelberg.de/volltextserver/19026/1/Thesis_Koser_HeiDOK.pdf; urn:nbn:de:bsz:16-heidok-190266; Koser, Franziska (2015) Role of the ubiquitin-proteasome system in the pathogenesis of cardiac hypertrophy and aging. [Dissertation]
    • الرقم المعرف:
      10.11588/heidok.00019026
    • الدخول الالكتروني :
      https://archiv.ub.uni-heidelberg.de/volltextserver/19026/
      https://archiv.ub.uni-heidelberg.de/volltextserver/19026/1/Thesis_Koser_HeiDOK.pdf
      https://doi.org/10.11588/heidok.00019026
      https://nbn-resolving.org/urn:nbn:de:bsz:16-heidok-190266
    • Rights:
      info:eu-repo/semantics/openAccess ; http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
    • الرقم المعرف:
      edsbas.85D94F70