Loss of proteostasis as a substrate for atrial fibrillation: Defining novel targets for therapy

Roelien Meijering

    Research output: ThesisThesis fully internal (DIV)

    765 Downloads (Pure)

    Abstract

    Atrial fibrillation (AF) is the most common sustained clinical tachyarrhythmia associated with increased mortality and morbidity. Conventional treatment options against AF still lack efficacy and are ineffective in preventing the recurrence of AF. Understanding cellular processes involved in the initiation, maintenance and progression of AF are necessary for the development of new therapies for AF. In this thesis we investigated the cellular processes that contribute to AF, with a central role for the derailment of proteostasis. Derailment of proteostasis is defined as the loss of protein homeostasis, which is necessary for the maintenance of normal cardiac function. The derailment affects processes controlling the concentration, conformation, binding-interaction, kinetics, and location of individual proteins. In addition to contributing to AF induction, derailment of proteostasis is aggravated by AF itself, resulting in electrical and structural remodeling of the cardiomyocyte, subsequently leading to AF progression. New therapeutic intervention strategies aimed at preventing derailment of proteostasis were shown successful in preventing AF in our experimental models. Our data indicate that loss of proteostasis represents an important determinant of AF pathology and conservation of cardiac proteostasis. Inhibitors of HDAC6, RhoA-GTPase, ER stress and HSP inducing compounds as potential new therapeutic strategies for AF.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Henning, Rob, Supervisor
    • Brundel, Bianca, Co-supervisor
    Award date2-Jun-2014
    Place of Publication[S.l.]
    Publisher
    Print ISBNs978-90-367-6973-0
    Electronic ISBNs978-90-367-6972-3
    Publication statusPublished - 2014

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