Medicine and Health Sciences Commons^™

Unique Transcriptional Profile Of Sustained Ligand-Activated Preconditioning In Pre- And Post-Ischemic Myocardium, Kevin Ashton, Amanda Tupicoff, Grant Williams-Pritchard, Can Kiessling, Louise See Hoe, John Headrick, Jason Peart

Kevin Ashton

Background: Opioidergic SLP (sustained ligand-activated preconditioning) induced by 3–5 days of opioid receptor (OR) agonism induces persistent protection against ischemia-reperfusion (I-R) injury in young and aged hearts, and is mechanistically distinct from conventional preconditioning responses. We thus applied unbiased gene-array interrogation to identify molecular effects of SLP in pre- and post-ischemic myocardium. Methodology/Principal Findings: Male C57Bl/6 mice were implanted with 75 mg morphine or placebo pellets for 5 days. Resultant SLP did not modify cardiac function, and markedly reduced dysfunction and injury in perfused hearts subjected to 25 min ischemia/45 min reperfusion. Microarray analysis identified 14 up- and 86 down-regulated …

Selective Effects Of Intrinsic A2aar Activity On Cardiac And Coronary Injuries With Lps Challenge, Melissa Reichelt, Kevin Ashton, S Mustafa, B Tang, Catherine Ledent, Xing Tan, John Headrick, R Morrison

Kevin Ashton

We assessed the impact of A2A adenosine receptor (A2AAR) knockout (KO) on LPS-triggered cardiovascular injuries, inflammation, gene expression and mortality. LPS precipitated cardiac injury, with 7-fold elevations in serum cardiac troponin I (cTnI) and 25–35% reductions in ventricular contractility. Coronary dysfunction was evident as a 20% reduction in reactive hyperaemic flows. A2AAR KO augmented cTnI release 3-fold without modifying ventricular dysfunction. Coronary effects of LPS and A2AAR KO were identical, and LPS no longer modified hyperaemia in A2AAR KO hearts. Effects of A2AAR activity were largely independent of shifts in acute phase reactants (CRP, haptoglobin) and circulating cytokines. Thus, up …

Cardiovascular Adenosine Receptors: Expression, Actions And Interactions, John Headrick, Kevin Ashton, Roselyn Rose'meyer, Jason Peart

Kevin Ashton

Intra- and extracellular adenosine levels rise in response to physiological stimuli and with metabolic/energetic perturbations, inflammatory challenge and tissue injury. Extracellular adenosine engages members of the G-protein coupled adenosine receptor (AR) family to mediate generally beneficial acute and adaptive responses within all constituent cells of the heart. In this way the four AR sub-types—A1, A2A, A2B, and A3Rs—regulate myocardial contraction, heart rate and conduction, adrenergic control, coronary vascular tone, cardiac and vascular growth, inflammatory–vascular cell interactions, and cellular stress-resistance, injury and death. The AR sub-types exert both distinct and overlapping effects, and may interact in mediating these cardiovascular responses. The …

The Adenosine A2a Receptor — Myocardial Protectant And Coronary Target In Endotoxemia, Melissa Reichelt, Kevin Ashton, Xing Tan, S Mustafa, Catherine Ledent, Lea Delbridge, Polly Hofmann, John Headrick, R Morrison

Kevin Ashton

Background: Cardiac injury and dysfunction are contributors to disease progression and mortality in sepsis. This study evaluated the cardiovascular role of intrinsic A2A adenosine receptor (A2AAR) activity during lipopolysaccharide (LPS)-induced inflammation.

Methods: We assessed the impact of 24 h of LPS challenge (20 mg/kg, IP) on cardiac injury, coronary function and inflammatory mediator levels in Wild-Type (WT) mice and mice lacking functional A2AARs (A2AAR KO).

Results: Cardiac injury was evident in LPS-treated WTs, with ~ 7-fold elevation in serum cardiac troponin I (cTnI), and significant ventricular and coronary dysfunction. Absence of A2AARs increased LPS-provoked cTnI release at 24 h by …