Mineralocorticoid receptor activation is crucial in the signaling pathway to the Anrep effect.

CALDIZ CI - DÍAZ RG; ENNIS IL; CHIAPPE DE CINGOLANI G; CINGOLANI HE; PÉREZ NG

THE JOURNAL OF PHYSIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2011 vol. 589 p. 6051 - 6061

0022-3751

The increase in myocardial reactive oxygen species (ROS) after epidermal growth factor receptor(EGFR) transactivation (TSA) is a crucial step in the autocrine/paracrine angiotensin II (AngII)/endothelin (ET) receptor activation leading to the slow force response to stretch (SFR). Sinceexperimental evidence suggests a link between Ang II or its receptor AT1 and themineralocorticoid receptor (MR), and MR transactivates the EGFR, we thought to determinewhether MR activation participates in the SFR development in rat myocardium. MR activation isnecessary to promote ROS formation by a physiological concentration of Ang II (1 nmol/L),since a ROS increase of ~50% of basal was cancelled by blocking MR with spirolactone (Sp) oreplerenone (Ep). This effect was also cancelled by blocking AT1, ET (ETA) or EGF receptors, byinhibiting NADPH oxydase (apocynin) or by targeting mitochondria, and was unaffected byglucocorticoid receptor inhibition. All interventions except AT1 receptor blockade blunted theROS-promoted effect of an equipotent dose of ET-1 (1 nmol/L) confirming that ETA activation isdownstream AT1. Similarly, ROS promoted by an equipotent dose of ALD (10 nmol/L) werecancelled by Sp or Ep, by preventing EGFR TSA, but not by inhibiting glucocorticoid receptorsor protein synthesis, suggesting nongenomic MR effects. ALD+ET-1 did not increase ROSformation more than each agonist separately. ALD increased phosphorylation of ROS-sensitivekinases (ERK1/2-p90RSK) and NHE-1. These effects were cancelled by Ep or by preventingEGFR TSA. Finally, the SFR was cancelled by MR blockade, by preventing EGFR TSA or byscavenging ROS, but unaffected by glucocorticoid receptor blockade or protein synthesisinhibition. These results suggest that MR activation is a necessary step in the stretch-triggeredROS-mediated activation of redox-sensitive kinases upstream NHE-1.