The sodium pump is a membrane protein that is critical for the function of all cells, but particularly those in the heart.

Its level of activity determines the concentration of sodium and calcium in the cell, which has important effects on the ability of heart cells to contract and the heart’s susceptibility to arrhythmia. In the smooth muscle cells found in blood vessels, the activity of the sodium also contributes to the regulation of blood vessel tone.

Researchers at Royal North Shore Hospital have identified a novel mechanism of regulation of the sodium potassium pump that is important in healthy hearts and blood vessels as well as pathological conditions. This discovery has led to a number of current parallel projects funded by the Foundation, further characterizing this signalling pathway and examining for novel therapeutic targets that may be important for future management of heart failure, hypertension and ischemic heart disease.

In the past year, Heart Research Australia has funded several projects in this novel research area:

Project title: Protein oxidative modification measurement by ELISA

Summary: Increasing oxidative stress can lead to the modification of the ATP-dependent Na+-K+ pump, an important and ubiquitous molecular pump that is vital for maintaining the intracellular chemical environment. This study is investigating the role of the novel modification of the pump in the pathogenesis of cardiovascular diseases (CVD). This project will also examine the Na+-K+ pump in blood cells as a non-invasive marker of the degree of oxidative stress in the cardiovascular system.

This will improve insight into the important link between oxidative stress and CVD, and may allow new prognostic markers and therapeutic targets for CVD to be identified.

Investigators: Dr Chia Chi Liu, Alvaro Garcia, Dr Gemma Figtree, Prof Helge Rasmussen

Funded since: 2011

Project title: Phospholemman: a rescue protein in heart attack

Summary: The research team have recently identified reactive oxygen species as key in the regulation of the Na+-K+ pump. They have found that the protein phospholemman (also known as FXYD1), which is associated with the pump in the membrane of heart cells, is able to reduce the amount of pump inhibition induced by oxidative stress. Given oxidative stress plays a key role in the heart damage seen at the time of heart attack, and elevated sodium within the heart cell has an important patho-physiological role, they have examined the therapeutic potential of recombinant phospholemman protein at the time of heart attack. In the first six months of this project they have optimised production of the recombinant protein, as well as its delivery in a model of heart attacks. The next aim is to examine the effects of delivery on the size of infarction (region of heart attack), and heart function.

Investigators: Dr Gemma Figtree, Professor Helge Rasmussen

Associate investigators: Dr Chia Chi Liu, Dr Andrea Nunez.

Funded since: 2011

Project title: ACE inhibitor, ß-blockers and the Na+-K+ pump

Summary: Initial in vitro work has demonstrated that the neurohormone angiotensin II and adrenergic hormones inhibit the cardiac Na+-K+ pump by “oxidizing” the pump’s beta1 subunit. In order to assess the physiological significance of this in vivo resesarchers have examined the effect of administering oral medication designed to inhibit these pathways to healthy subjects. They have found that this results in a reduction of baseline oxidative inhibition of the Na+-K+ pump, and are now investigating the impact of this in heart failure.

Investigator: Prof Helge Rasmussen

Funded since: 2011

Project title: Natriuretic peptide-induced oxidative modification of the Na+-K+ pump

Summary: Natriuretic peptides and their receptors (NPRs) are expressed in the heart, but their effects on heart cell function are poorly understood. Researchers have examined the mechanisms by which atrial natriuretic peptide (ANP) regulates the pump. They have found that low concentrations of ANP stimulate the Na+-K+ pump and this is abolished by inhibition of the enzyme NO synthase. However, at higher concentrations, as may be seen in heart failure, ANP induces ß1 subunit glutathionylation (oxidation) resulting in pump inhibition. These results are important for our understanding of the basic mechanism of Na+-K+ pump regulation. Because heart failure is characterised by dysregulation of NO synthesis, increased oxidative stress in the myocardium and raised myocyte Na+ levels, as well as elevated natriuretic peptide levels, these results also have implications for our understanding of these pathophysiological processes and for potential identification of novel therapeutic targets.

Investigator: Dr Elisha Hamilton

Funded since: 2011

Project title: Oxidant signalling via S-Glutathionylation of reactive cysteines in the NaK ATPase and Phospholemman protein complex

Summary: This research has recently shown that the addition of a small protein (glutathione) has a significant effect on the activity of the sodium pump. The addition of the glutathione protein to the pump is the end effect of an oxidant signalling cascade in the heart cell. The aim of this project is to understand how this small protein addition can have such a profound effect on pump activity and to try to understand how this fits into heart cells’ day-to-day function.

PhD candidate: Alvaro Garcia

Supervisor: Prof Helge Rasmussen

Funded since: 2011