Protecting the heart from ischaemia-reperfusion injury: a new role for FXYD proteins?

Summary

We are interested to have a PhD student join our team at the Kolling Institute, examining the therapeutic potential of FXYD proteins in a model of heart attack/myocardial infarction. We have published data demonstrating a key role of these proteins in reversing oxidative inhibition of the cardiac Na+-K+ pump. Recent preliminary data from our Laboratory has shown that parenteral administration results in successful delivery of recombinant FXYD proteins to the heart. The project will examine the effect of such administration on molecular, and physiological parameters in a model of myocardial ischaemia/reperfusion.

Supervisor(s)

Associate Professor Gemma Figtree

Research Location

North Shore - Kolling Institute of Medical Research

Program Type

PHD

Synopsis

Background: Although outcomes of patients with myocardial infarction have improved with rapid revascularization, reperfusion itself can result in injury to the myocardium. Factors contributing to such ischaemia reperfusion (IR) injury include oxidative stress, inflammation, microvascular dysfunction, calcium malhandling and apoptosis. In an animal model of myocardial IR, we have observed increased glutathionylation, an oxidative modification of the Na-K pump's beta1 subunit. As this inhibits the Na-K pump, we postulate that this is a key contributor to elevated Na, and secondarily via the Na-Ca exchanger, to Ca overload, activation of Ca-dependent proteases and myofibril proteolysis. Pilot studies have found that FXYD1, a small, lipid soluble protein that colocalises with the Na-K pump, protects the pump from oxidative inhibition. Recombinant FXYD (rFXYD) inserts correctly in the membrane with native pump subunits and reaches the heart rapidly after intraperitoneal injection. This study will examine the therapeutic potential of rFXYD1 in myocardial IR injury.

Experimental approach: The effects of rFXYD1 on cell injury and death will first be characterized in a cell model of IR. In vivo dose and delivery optimization will be performed using rFXYD1 tagged with Cy5 and a Fe cross-linked nanoparticle, imaged by both fluorescent and magnetic resonance modalities. The effects of rFXYD1 on infarct size, cardiac remodeling and function will be examined using histological and imaging methods in a mouse (including FXYD1 KO) and rabbit model of IR. rFXYD with no cysteines will be used as a control, with a dominant negative effect resulting from competitive displacement of native FXYD.

Outcomes and significance: Oxidative inhibition of the Na-K pump contributes to increases in Na and Ca and associated tissue injury in the setting of myocardial IR. rFXYD1 protects the Na-K pump from glutathionylation, and has the potential to improve outcomes following myocardial infarction.

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Keywords

myocardial reperfusion injury, oxidative stress, sodium-potassium ATPase, reactive oxygen species (ROS), nuclear magnetic resonance (NMR), membrane signalling

Opportunity ID

The opportunity ID for this research opportunity is: 1424

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