Doctor of Philosophy, The Ohio State University, 2016, 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 in (open full item for complete abstract)

Committee: Peter Mohler (Advisor); Noah Weisleder (Committee Chair); Thomas Hund (Committee Member); Philip Binkley (Committee Member) Subjects: Cellular Biology; Physiology