Restricted diffusion of ions regulates cardiac function
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AbstractCardiac contractility is largely regulated through transients in intracellular Ca2+ concentration ([Ca2+]i). [Ca2+]i is under the influence of the sarcolemmal Na+/Ca2+-exchanger, which is regulated by the intracellular Na+ concentration ([Na+]i). The Na+/K+-ATPase is the main regulator of [Na+]i. Consequently, the Na+/K+-ATPase affects cardiac contractility. The Na+/K+-ATPase is composed by one catalytic a- and one regulatory β-subunit, and the function of the Na+/K+-ATPase depends mainly on the α-isoform present. Rat cardiomyocytes have two different α-isoforms (a1 and a2), but their respective role in the regulation of cardiac contractility is unclear. In the present thesis in cardiac physiology, Swift and coworkers have used immunohistochemical and electrophysiological techniques to study the localization of the Na+/K+-ATPase α-isoforms and how they influence Na+/Ca2+-exchange in isolated cardiomyocytes from the rat left ventricle. Also, using detubulation, the role of the t-tubules was assessed. The Na+/K+-ATPase a2-isoform constitutes only ~11% of all the Na+/K+-ATPases in rat cardiomyocytes. However, by localisation in discrete locations in the t-tubules of the cardiomyocyte, the α2-isoform is efficiently coupled to the Na+/Ca2+-exchanger. This occurs through a subsarcolemmal pool of Na+, and constitutes an important regulatory mechanism of cardiomyocyte contractility. Altered t-tubule network structure and downregulation of the α2-isoform in a rat post infarction congestive heart failure model cause attenuated control of Na+/Ca2+-exchanger activity, presumably due to local alterations in [Na+]i. This indicates that the Na+/K+-ATPase α2-isoform is necessary to modulate [Na+]i close to the Na+/Ca2+-exchanger. Downregulation of Na+/K+-ATPase α2-isoform might therefore constitute a molecular basis for altered contractile properties in the failing heart.
List of papers
|Paper 1: Slow diffusion of K+ in the t-tubules of rat cardiomyocytes. Fredrik Swift, Tævje A. Strømme, Bjørn Amundsen, Ole M. Sejersted, Ivar Sjaastad Journal of Applied Physiology 2006;101:1170-6 The paper is not available in DUO. The published version is available at: https://doi.org/10.1152/japplphysiol.00297.2006|
|Paper 2: The Na+/K+-ATPase α2-isoform regulates cardiac contractility in rat cardiomyocytes. Fredrik Swift, Nils Tovsrud, Ulla H. Enger, Ivar Sjaastad, Ole M. Sejersted Cardiovascular Research 2007;75:109-17. The paper is not available in DUO. The published version is available at: https://doi.org/10.1016/j.cardiores.2007.03.017|
|Paper 3: Altered regulation of Na+/Ca2+-exchanger activity due to downregulation of Na+/K+-ATPase2-isoform in cardiomyocytes from rats with post infarction congestive heart failure Submitted manuscript Fredrik Swift, Jon Arne Kro Birkeland, Nils Tovsrud, Ulla H. Enger, Jan Magnus Aronsen, William E. Louch, Ivar Sjaastad, Ole M. Sejersted. The paper is not available in DUO.|