Cardioprotective effect of acute hydrocortisone therapy against ischemia/reperfusion injury involves Akt - triggered antioxidant effects

ESCUDERO DS; FANTINELLI JC; MARTINEZ V; GONZÁLEZ ARBELÁEZ LF; PÉREZ NG; DÍAZ RG

Mendoza

Congreso; XL Congreso Naconal de Cardiologia - FAC 2023; 2023

FAC-GADOR

Corticosteroid therapy was used in the prophylaxis of atrial fibrillation following cardiac surgery or acute myocardial infarction (AMI). However, high doses of corticosteroids are associated with increased cardiac arrhythmias and contractile dysfunction. Glucocorticoid (GR) and mineralocorticoid (MR) receptors (highly expressed in myocardium) are both activated by corticosteroids. While MR activation in a context of AMI was linked to increased infarct size and contractile dysfunction, little is known about the possible effects of GR activation. This studywas aimed to explore the role of an acute dose of a low potency corticosteroid (hydrocortisone, HC, 10nM) in a rat model of AMI. Isolated hearts from Wistar rats were subjected to 40 minutes of regional ischemia followed by 60 minutes of reperfusion in absence (ischemic control I, n=4) or presence of HC (n=4) added during first 10 minutes of reperfusion. HC reduced the infarct size (In % risk area: 38±3 I vs. 9±3 HC, p< 0.05) and the increased oxidative stress promoted by AMI(Figure 1a and 1b), evidenced by the decreased reactive oxygen species generation (In IF/mg tissue: 85±4 I vs. 45±5 HC, p< 0.05) and lipid peroxidation (TBARS in nm/MDA/mg tissue: 5±0.5 I vs. 2±0.07 HC, p< 0.05), as well as by the increased GSH/GSSG ratio (In µg/mg tissue: 0.7±0.05 I vs. 1.9±0.21 HC, p< 0.05). Furthermore, a significant increase in the expression of the mitochondrial fusion protein MFN-2 in hearts treated with HC was detected (in % of non-ischemic control: 44±8 I, 126±9 HC, p< 0.05). Those effects were avoided by blocking GR with Mifepristone. Isolated papillary muscles from non-infarcted hearts were used to evaluate NHE1 activity in absence and presence of HC by analyzing intracellular pH recovery from an acute transient acidosis (TA). HC reduced NHE1 activity (maximal H+ efflux in mmol/ml/min: 1.22±0.19 TA vs. 0.56±0.15 HC, p< 0.05), did not affect NHE1 expression, but significantly increased the NHE1 pro-inhibitingSer648 phosphorylation (in % of control: 102.1±7TA, 155.0±23.3HC10, p< 0.05) and its upstream cardioprotective kinase AKT (in % of control: 102±19TA, 202±24HC10, p< 0.05). In connection, AKT phosphorylation level decreased after AMI and was recovered by HC (in % of non-ischemic control: 37±1 I, 150±22 HC, p< 0.05, Figure 1c). Finally, AMI reduced the expression of the antiapoptotic protein BCL-2, effect that was abrogated by HC (in % of non-ischemic control: 42±3 I,106±6 HC, p< 0.05). In conclusion, our results provide first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI. This cardioprotection is associated with a non-genomic HC-triggered antioxidant action that involves mitochondrial dynamics improvement and AKT-induced NHE1 inhibiti