Abstract 12647: Acute Glucocorticoid Receptor Activation Induces Rat Heart Cardioprotection Against Infarction Through Na+/h+ Exchanger Regulation

Abstract

Introduction: Acute corticosteroid therapy has been used in the prophylaxis against atrial fibrillation following cardiac surgery or acute myocardial infarction (AMI). Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue. While MR activation during AMI was linked to Na + /H + exchanger (NHE1) activation-mediated increase in infarct size and contractile dysfunction, lesser is known about GR effects. The aim of this work is to seek the functional effects of an acute dose of a low potency corticosteroid (hydrocortisone, HC) in a rat model of AMI. Methods: AMI was promoted in isolated hearts from Wistar rats by 40min of regional ischemia followed by 60min reperfusion (ischemic control “I”, n=4). 10nM HC (HC10, n=3) or HC10 plus the GR inhibitor Mifepristone (M, 10uM, n=5) was added to the perfusate during the first 10min of reperfusion. In isolated papillary muscles from non-infarcted hearts NHE1 activity was measure by analyzing the pH recovery from an acute transient acidosis (TA) in control conditions, and in the presence of HC 1nM (HC1) or HC10. Protein phosphorylation and expression were determined by western blot. Data are expressed as mean±S.E.M. Results: HC treatment reduced infarct size (% of risk area: 38±3 I; 9±3 HC10, p<0.05, t-test), improved left ventricular developed pressure, LVDP (% of preischemic control: 28±4 I vs. 60±5 HC10, P<0.05, t-test) and decreased left ventricular end diastolic pressure, LVEDP (in mmHg: 55±4 I vs. 28±5 HC, P<0.05, t-test). M avoided HC protective effects (infarct size 24±4%; LVDP 34±10%; LVEDP 10±2 mmHg). HC reduced NHE1 activity (JH+ in mmol/ml/min: 1.22±0.19 TA, n=5; 0.68±0.11 HC1, n=4; 0.56±0.15 HC10, n=4, p<0.05, ANOVA). Neither NHE1 expression nor the NHE1 pro-activating Ser703 phosphorylation were modified. HC10 increased NHE1 pro-inhibiting Ser648 phosphorylation (% of control: 102±7 TA, 111±16 HC1, 155±23 HC10, n=8, p<0.05, ANOVA). In line, AKT phosphorylation level was increased by HC (% of control: 102±18 TA, 160±20 HC1, 202±24 HC10; n=9, p<0.05, ANOVA). Conclusions: Our results show that HC induce cardiac protection against AMI via GR activation, through a mechanism that may be assigned to an inhibitory AKT-mediated Ser648 NHE1 phosphorylation.