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Makara Dissertation 2-22-16.pdf (5.47 MB)

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Molecular physiology of ankyrin-G in the heart: Critical regulator of cardiac cellular excitability and architecture.

Makara, Michael A
http://rave.ohiolink.edu/etdc/view?acc_num=osu1455812677

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Cardiovascular disease is the leading cause of death in the United States, claiming nearly 800,000 lives each year. Regardless of the underlying cardiovascular dysfunction, nearly 50% of these patients die of sudden cardiac arrest caused by arrhythmia. Development and sustainment of cardiac arrhythmia begins with dysfunction of excitability and structure at the cellular level. Therefore, in order to improve therapeutic options for these patients, a basic understanding of the molecular mechanisms regulating cardiac cellular excitability and structure is required. Decades of research have demonstrated that intracellular scaffolding polypeptides known as ankyrins are critical for the regulation of cellular excitability and structure in multiple cell types. Ankyrin-G (ANK3) is critical for regulation of action potentials in neurons and lateral membrane development in epithelial cells. Given its central importance for cellular physiology in excitable and non-excitable cell types, we hypothesized that functional ankyrin-G expression is critical for proper cardiac function. To test this hypothesis in vivo, we generated cardiac-specific ankyrin-G knockout (cKO) mice. In the absence of ankyrin-G, mice display significant reductions in membrane targeting of the voltage-gated sodium channel Nav1.5. This disruption in turn causes severely reduced whole cell sodium current, leading to significant conduction abnormalities, bradycardia, and ventricular arrhythmia and atrioventricular nodal block following infusion of NaV channel antagonists. In addition to regulating cardiac excitability, we also demonstrate a critical role for ankyrin-G in the regulation of the cardiomyocyte cytoarchitecture. Specifically, ankyrin-G cKO mice show disrupted cellular distribution of the desmosomal protein plakophilin-2 (PKP2) at baseline. In a setting of pressure overload-induced heart failure we observed severe disruptions to the cellular localization of PKP2. Further, as desmosomes mediate the integration of the intermediate filament protein desmin, we demonstrate the reduced expression of desmin at the intercalated disc (ID) in the setting of mislocalized PKP2. Mechanistically, we correlate these molecular changes with significant reductions in systolic function and increased propensity for bradyarrhythmia in ankyrin-G cKO mice following transverse aortic constriction (TAC). As ankyrin-G is significantly increased two weeks post TAC, we hypothesize that ankyrin-G expression is required for the early, compensatory phase of ventricular remodeling. Our hypothesis is further strengthened by the observation that functional ankyrin-G expression is severely reduced in multiple forms of human heart failure. We conclude that ankyrin-G is a critical regulator of both excitability and molecular architecture of the intercalated disc. We further hypothesize that remodeling of this ankyrin-G-dependent molecular environment is a critical step in the development of human arrhythmia and structural heart diseases.
Peter Mohler (Advisor)
Noah Weisleder (Committee Chair)
Thomas Hund (Committee Member)
Philip Binkley (Committee Member)
222 p.
Cellular Biology; Physiology
ankyrin; arrhythmia; heart; failure; sodium channel; plakophilin; CaMKII; spectrin; intercalated disc; late sodium current; cardiovascular disease; sudden cardiac arrest; SCN5A

Recommended Citations

Citations

  • Makara, M. A. (2016). Molecular physiology of ankyrin-G in the heart: Critical regulator of cardiac cellular excitability and architecture. [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1455812677

    APA Style (7th edition)

  • Makara, Michael. Molecular physiology of ankyrin-G in the heart: Critical regulator of cardiac cellular excitability and architecture. . 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1455812677.

    MLA Style (8th edition)

  • Makara, Michael. "Molecular physiology of ankyrin-G in the heart: Critical regulator of cardiac cellular excitability and architecture. ." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1455812677

    Chicago Manual of Style (17th edition)

osu1455812677
748
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This open access ETD is published by The Ohio State University and OhioLINK.