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Adenosine G Protein‐Coupled Receptor Biased Agonism to Treat Ischemic Heart Disease
Author(s) -
May Lauren Therese,
Baltos JoAnne,
Chuo Chung H.,
Vecchio Elizabeth A.,
Wang Bing H.,
Kompa Andrew R.,
Christopoulos Arthur,
Scammells Peter J.,
White Paul J.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.555.19
Subject(s) - cardioprotection , medicine , reperfusion injury , ischemia , agonist , context (archaeology) , pharmacology , cardiac function curve , adenosine , functional selectivity , cardiology , heart failure , receptor , biology , paleontology
Ischemic heart disease and secondary heart failure places an immense burden on society. Stimulation of adenosine G protein‐coupled receptors (ARs) represents a powerful protective mechanism to decrease cardiac ischemia‐reperfusion injury (IRI). Despite this, therapeutic targeting of ARs has been largely unsuccessful due to on‐target adverse effects, including pronounced bradycardia, atrioventricular block and hypotension (1). Biased agonism has the potential to overcome these limitations by enabling the separation of therapeutic from adverse effects (2). Aim To profile prototypical and biased AR agonism in isolated cardiac cells. Subsequent studies investigated the in vivo profile of AR biased agonism in acute and longer‐term rat models of cardiac ischemia‐reperfusion injury. Results In isolated rat cardiomyocytes, prototypical and biased AR agonists stimulated reperfusion injury salvage kinase (RISK) signalling pathways, including Akt and ERK1/2, and promoted cardioprotection. Exposure to in vitro simulated ischemia‐reperfusion conditions differentially influenced the RISK signalling stimulated by prototypical and biased AR agonists. Within an in vivo model of acute myocardial ischemia‐reperfusion injury, both biased and prototypical agonists stimulated an A 1 AR‐mediated reduction in infarct size and an improvement in cardiac function post‐IRI. However, in contrast to prototypical agonists, our biased agonist had no significant adverse hemodynamic effects. Furthermore, in a longer‐term in vivo model of myocardial IRI, an AR biased agonist improved cardiac function and decreased cardiac hypertrophy and fibrosis. Discussion Insights into AR signalling in cardiomyocytes under normoxic and simulated ischemia‐reperfusion conditions suggests that context‐specific biased agonism stimulates a preferential signalling profile. Furthermore, AR biased agonism can promote cardioprotection and decrease pathological cardiac remodelling in the absence of bradycardia, a profile suggestive of ligand bias. Collectively, our findings demonstrate that AR biased agonism can stimulate potent cardioprotection in the absence of adverse hemodynamic effects and therefore represents an attractive therapeutic approach for the treatment of ischemic heart disease. Support or Funding Information This work was supported by Project Grant APP1084487 of the National Health and Medical Research Council of Australia (NHMRC). J‐A.B., CHC and E.A.V are recipients of the Australian Government Research Training Program Scholarship. A.C. is a Senior Principal Research Fellow of the NHMRC. L.T.M. is an Australian Heart Foundation Future Leaders Fellow. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .