The role of the Na/K ATPase in heart failure

• Applicant: Petra Eder-Negrin, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274983355

Elevated Na+ levels in cardiomyocytes have been suggested as critical alteration accelerating the functional impairment in the course of heart failure development. Responsible for a Na+ dysregulation are mostly Na+ channels, transporters and exchangers in the sarcolemma with the Na/K ATPase (NKA) as the main Na+ extrusion protein. The NKA does not only affect the intracellular Na+ homeostasis [Na+]i by exporting Na+ against K+, but also regulates intracellular Ca2+ through the activity of the Na/Ca exchanger (NCX). Based on this cross-talk, cardiac glycosides have been used for centuries in the heart failure therapy with the aim to inhibit an NKA- mediated Na+ efflux, to block NCX activity and thus increase Ca2+ and contractility of cardiomyocytes. Despite its well-known pump function and its role as target for cardiac glycosides there are, however, uncertainties as to whether a depressed Na+ efflux is beneficial for the failing heart. Moreover, it has not been entirely resolved whether targeting different NKA isoforms affect cardiac function during heart failure progression to the same extent. In the heart there are two isoforms (NKA-alpha1 and NKA-alpha2) of the catalytic alpha- NKA subunit expressed. Aim of the proposed study is to analyse their respective roles in heart failure progression and to monitor cardiac function after inhibition of a given NKA isoform. To approach this task we will examine transgenic mouse models with increased expression of either NKA-alpha1 or NKA-alpha2 specifically in the heart. Heart failure will be induced by subjecting mice to chronic myocardial infarction (MI) injury. A cohort of mice will be treated with the NKA inhibitor digoxin at different time points during heart failure progression. Cardiac performance during MI treatment will be monitored regularly by echocardiography for eight weeks. Complementing the in vivo analyses, functional aspects will be determined in isolated cardiomyocytes from failing hearts by measuring intracellular Na+ and Ca2+ levels, the contractile performance and action potentials. Mechanistic links with signaling cascades and proteins in diseased hearts from NKA-alpha1 or NKA-alpha2 transgenic mice will be analysed in biochemistry which include proteins of the excitation- contraction coupling machinery and phosphoproteins that regulate Na/K ATPase function as well as downstream hypertrophic signaling pathways. Findings from these studies will increase our understanding of the Na/K ATPase as one of the most important Na+ regulatory protein in the heart and its role as therapeutic target in heart failure therapies.

• DFG Programme: Research Grants