Mineralocorticoid receptor activation is crucial in the signalling pathway leading to the Anrep effect

CALDIZ CI; DIAZ RG; NOLLY MB; CHIAPPE DE CINGOLANI GE; ENNIS IL; CINGOLANI HE; PÉREZ NG

THE JOURNAL OF PHYSIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2011 p. 6051 - 6061

0022-3751

Abstract The increase in myocardial reactive oxygen species after epidermal growth factorreceptor transactivation is a crucial step in the autocrine/paracrine angiotensin II/endothelinreceptor activation leading to the slowforce response to stretch (SFR). Since experimental evidencesuggests a link between angiotensin II or its AT1 receptor and the mineralocorticoid receptor(MR), and MR transactivates the epidermal growth factor receptor, we thought to determinewhether MR activation participates in the SFR development in rat myocardium. We show herethat MR activation is necessary to promote reactive oxygen species formation by a physiologicalconcentration of angiotensin II (1 nmol l−1), since an increase in superoxide anion formation of∼50% of basal was suppressed by blockingMR with spironolactone or eplerenone. This effect wasalso suppressed by blocking AT1, endothelin (type A) or epidermal growth factor receptors, byinhibiting NADPH oxydase or by targeting mitochondria, and was unaffected by glucocorticoidreceptor inhibition. All interventions except AT1 receptor blockade blunted the increase in superoxideanion promoted by an equipotent dose of endothelin-1 (1 nmol l−1) confirming that endothelinreceptors activation is downstream of AT1. Similarly, an increase in superoxide anionpromoted by an equipotent dose of aldosterone (10 nmol l−1) was blocked by spironolactone oreplerenone, by preventing epidermal growth factor receptor transactivation, but not by inhibitingglucocorticoid receptors or protein synthesis, suggesting non-genomicMR effects. Combinationof aldosterone plus endothelin-1 did not increase superoxide anion formation more than eachagonist separately. We found that aldosterone increased phosphorylation of the redox-sensitivekinases ERK1/2-p90RSK and the NHE-1, effects that were eliminated by eplerenone or by preventingepidermal growth factor receptor transactivation. Finally, we provide evidence that theSFR is suppressed byMRblockade, by preventing epidermal growth factor receptor transactivationor by scavenging reactive oxygen species, but it is unaffected by glucocorticoid receptor blockadeor protein synthesis inhibition. Our results suggest that MR activation is a necessary step in the stretch-triggered reactive oxygen species-mediated activation of redox-sensitive kinases upstreamNHE-1.