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Oxidative Regulation Of The Na Pump- A New Player In Vascular Function In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$504,427.00
Summary
Oxidative stress is a major player in hypertension, atherosclerosis, diabetes and ageing, but we have struggled to develop a therapy to successfully combat in heart and vascular cells in large clinical trials. We have discovered a new role for membrane protein FXYD1, to protect key heart and vascular proteins from functional impairment secondary to oxidative stress. We will investigate its role in protecting against vascular disease, and test novel therapies based on this endogenous protector.
Heart attacks remain a major cause of morbidity and mortality. I am an interventional cardiologist who heads an expanding basic and translational science laboratory (Cardiac Oxidative Signalling) at the Kolling Institute and who plays a leading role in clinical cardiovascular research at Royal North Shore Hospital. My vision is to translate fundamental discoveries in our Laboratory to new therapies and methods of risk stratification to improve immediate and long term outcomes of patients sufferi ....Heart attacks remain a major cause of morbidity and mortality. I am an interventional cardiologist who heads an expanding basic and translational science laboratory (Cardiac Oxidative Signalling) at the Kolling Institute and who plays a leading role in clinical cardiovascular research at Royal North Shore Hospital. My vision is to translate fundamental discoveries in our Laboratory to new therapies and methods of risk stratification to improve immediate and long term outcomes of patients suffering heart attack.Read moreRead less
Acute Exercise And Digoxin Effects On Skeletal Muscle Na+,K+ATPase Regulation, K+ Homeostasis And Fatigue In Humans:
Funder
National Health and Medical Research Council
Funding Amount
$177,000.00
Summary
This grant investigates the regulation of an enzyme in skeletal muscle referred to as the sodium-potassium pump, since its function is to pump potassium into the cell and sodium out of the cell. This enzyme is vital in enabling the muscles to contract and plays a key role in supporting our capacity to exercise. Our studies have suggested that acute exercise depresses the maximal capacity (activity) of this enzyme, thereby rendering the muscle liable to fatigue. We examine whether a well-defined ....This grant investigates the regulation of an enzyme in skeletal muscle referred to as the sodium-potassium pump, since its function is to pump potassium into the cell and sodium out of the cell. This enzyme is vital in enabling the muscles to contract and plays a key role in supporting our capacity to exercise. Our studies have suggested that acute exercise depresses the maximal capacity (activity) of this enzyme, thereby rendering the muscle liable to fatigue. We examine whether a well-defined exercise leading to fatigue, does inhibit the sodium-potassium pump and whether recovery occurs within 3 hours after exercise. The sodium-potassium pump is comprised of several variations of very similar enzymes, known as isoforms, each under the control of a separate gene and having slightly different functions and regulation. We explore whether exercise causes the genes regulating these isoforms to be activated and whether this results in an increased isoform formation in the muscle cell. We use a drug commonly used in patients with heart failure, called digoxin, which blocks the action of the sodium-potassium pump. In rat muscles this reduces muscular performance, with earlier and more pronounced fatigue. We examine whether a similar detrimental effect occurs in muscles of exercising humans and measure the resultant effects on muscle sodium and potassium levels. Increased knowledge about the effects of a single exercise bout on muscle is important fundamental knowledge. The study will lead to new knowledge about sodium-potassium pump regulation in exercising humans and thus enhance our understanding of muscle fatigue and gene responses to exercise. Understanding exercise effects will assist in development of strategies to counter physical inactivity, which is a major burden on health in Australia. Improved understanding of the actions of digoxin will also benefit patients with heart failure, through modified drug use and development of more specific treatment.Read moreRead less
Regulation Of The Sarcolemmal Na-K Pump By FXYD Proteins
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
Background. Pump molecules embedded in the membranes of all cells maintain a difference in composition between the cell content and the surrounding tissue fluids. Of these, the membrane sodium-potassium pump (Na+-K+ pump) is the most important. It uses metabolic energy generated in the cell to transport 3Na+ out in exchange for 2K+ transported in, and maintains a low concentration of Na+ and a high concentration of K+ within cells. The opposite applies to the surrounding tissue fluids. The conce ....Background. Pump molecules embedded in the membranes of all cells maintain a difference in composition between the cell content and the surrounding tissue fluids. Of these, the membrane sodium-potassium pump (Na+-K+ pump) is the most important. It uses metabolic energy generated in the cell to transport 3Na+ out in exchange for 2K+ transported in, and maintains a low concentration of Na+ and a high concentration of K+ within cells. The opposite applies to the surrounding tissue fluids. The concentration gradient for Na+ serves in mechanisms that couple transport of other ions and molecules to the downhill movement of Na+ in the direction determined by its concentration gradient. The transport of ions and molecules directly and indirectly due to the operation of the membrane Na+-K+ pump is very important for the function of all cells. Objectives. It is poorly understood how cells regulate the activity of their membrane Na+-K+ pumps. We will examine if small molecules (FXYD proteins) in the cell membrane, closely associated with the pump, regulate its activity. Methods. We will use a whole-cell patch clamping technique to attach small glass pipettes to single heart cells and replace their content with solutions in the pipettes. The technique allows real-time measurement of Na+-K+ pump activity because the 3:2 Na+:K+ exchange ratio generates an electrical current that can be measured in the single cells. The FXYD proteins will be produced in bacteria, purified and introduced into the heart cells by inclusion in the pipette solution that replace the cell content. Expected outcomes. Achieving this project's objectives will greatly enhance our understanding of Na+-K+ pump regulation. This is important because high levels of Na+ in heart cells is a pivotal abnormality in heart disease. Understanding the Na+-K+ pump can be activated to reduce cell Na+ levels should help design of treatments.Read moreRead less
Effects Of Atrial Natriuretic Peptide On The Sarcolemmal Na-K Pump In Rabbit Myocytes
Funder
National Health and Medical Research Council
Funding Amount
$225,500.00
Summary
The sodium pump transports sodium ions across cell membranes from the inside of cells to the outside. This maintains the concentration of sodium more than ten-fold lower on the inside than the outside. This transmembrane concentration gradient is essential for normal cell function. It is well established that the sodium pump is regulated by a variety of hormones. In a pilot study we have demonstrated that a hormone secreted by the heart, atrial natriuretic peptide, stimulates the sodium pump in ....The sodium pump transports sodium ions across cell membranes from the inside of cells to the outside. This maintains the concentration of sodium more than ten-fold lower on the inside than the outside. This transmembrane concentration gradient is essential for normal cell function. It is well established that the sodium pump is regulated by a variety of hormones. In a pilot study we have demonstrated that a hormone secreted by the heart, atrial natriuretic peptide, stimulates the sodium pump in single heart cells. This has not been reported previously. This study will examine the cellular mechanisms that mediate the stimulation of the sodium pump by atrial natriuretic peptide. A study on the effect of atrial natriuretic peptide on the regulation of sodium in heart cells is particularly important from the perspective of heart failure, a condition characterised by an inability of the heart to pump a sufficient amount of blood. While the underlying causes of heart failure vary widely activation of several hormone systems is a common feature regardless of the aetiology. It has already been well established in clinical practice that interfering with hormone activation by drugs improves symptoms as well as survival. Drugs have recently been developed that can increase levels of atrial natriuretic peptide. Since raised levels of sodium may contribute to important heart cell abnormalities in heart failure the effect of atrial natriuretic peptide on sodium export from the cells by the pump may have important implications for treatment of this serious and common condition.Read moreRead less
Reversing Oxidative Inhibition Of The Na-K Pump By Beta3 Adrenergic Agonists: Implications For Heart Failure Therapy
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Heart failure is a debilitating condition characterised by a decreased heart pump function. Raised Na+ levels and increased oxidative stress in cardiac cells are important in its causation. While traditional antioxidants are not useful in treatment, we have found that a group of drugs designed to induce weight loss can reverse oxidative inhibition of the mechanism that pumps Na+ out of heart cells. The effect of these drugs on the Na+ pumping mechanism and heart failure will be examined.