Recombinant Human Neuregulin-1 in Myocardial Ischaemia-Reperfusion Injury and Chronic Heart Failure

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Copyright: Jabbour, Andrew
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Abstract
Neuregulin-1, a ligand of the ErbB family of receptor tyrosine kinases is produced by endocardial and myocardial microvascular endothelial cells and acts in a paracrine fashion on adjacent cardiac myocytes. Neuregulin-1-ErbB signalling critically regulates cardiac development and the adaptation of the heart to injury; inhibiting apoptosis, inducing cardiomyocyte proliferation and improving cardiac function and survival in animal models of cardiomyopathy.Neuregulin-1-ErbB signalling also involves pathways involved in protecting against ischaemia-reperfusion injury. This thesis reports the first human studies exploring the acute and chronic haemodynamic responses to a series of recombinant human Neuregulin-1 (rhNeuregulin-1) infusions in patients with stable chronic heart failure and also reports a series of studies aimed at enhancing cardiac preservation in heart transplantation by rhNeuregulin-1 supplementation of a cardiac storage solution. During a 6-hour rhNeuregulin-1 infusion cardiac output increased by 30% (p<0.01), pulmonary artery wedge pressure and systemic vascular resistance decreased 30% and 20% respectively at two hours (p<0.01). A 47% reduction in serum noradrenaline, a 55% reduction in serum aldosterone and a 3.6-fold increase in N-terminal fragment of B-type natriuretic peptide levels were concurrently observed (p<0.001). These acute haemodynamic effects were sustained, as demonstrated by a 12% increase in left ventricular ejection fraction from 32.2±2.0% (baseline) to 36.1±2.3% (mean±1SE, p<0.001) at 84 days. The therapy was well tolerated. In a rodent model of global ischaemia-reperfusion injury, rhNeuregulin-1 supplemented Celsior storage solution improved functional recovery of hearts after 6 hours of hypothermic storage, an effect abrogated by the phosphatidylinositol-3-kinase inhibitor, wortmannin. When storage times were extended out to 10 hours, rhNeuregulin-1 further enhanced cardiac preservation when used in combination with other activators of pro-survival pathways (p<0.01). Functional improvements were accompanied by increased phosphorylation of Akt, extracellular signal-regulated protein kinases 1/2, signal transducer and activator of transcription 3 and glycogen synthase kinase 3β (Western blotting) and a reduction in the cleaved form of caspase-3 (immunohistochemical staining). rhNeuregulin-1produces favourable acute and chronic haemodynamic effects in patients with stable chronic heart failure on optimal medical therapy and improves preservation of the rat heart after prolonged hypothermic storage. It shows promise as a novel therapy in heart failure and transplantation.
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Author(s)
Jabbour, Andrew
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Macdonald, Peter
Hayward, Christopher
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Publication Year
2010
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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