Myocardial Mineralocorticoid Receptor Activation by Stretching and Its Functional Consequences

DIAZ RG; PÉREZ NG; MORGAN PE; VILLA-ABRILLE MC; CALDIZ CI; NOLLY MB; PORTIANSKY EL; ENNIS IL; CINGOLANI HE

HYPERTENSION

LIPPINCOTT WILLIAMS & WILKINS

Lugar: Philadelphia; Año: 2014 vol. 63 p. 112 - 118

0194-911X

Myocardial stretch triggers an angiotensin II (Ang II)-dependent autocrine/paracrine loop of intracellular signals leading to reactive oxygen species (ROS)-mediated activation of redox-sensitive kinases. Based on pharmacological strategies we previously proposed that mineralocorticoid receptor (MR) is necessary for this stretch-triggered mechanism. Now, we aimed to test the role of MR after stretch by using a molecular approach to avoid secondary effects of pharmacological MR blockers. Small hairpin interference RNA capable to specifically knockdown the MR was incorporated into a lentiviral vector (l-shMR) and injected into the left ventricular wall of Wistar rats. The same vector but expressing a non-silencing sequence (scramble) was used as control. Lentivirus propagation through the left ventricle was evidenced by confocal microscopy. Myocardial MR expression, stretch-triggered activation of redox-sensitive kinases (ERK1/2-p90RSK), the consequent Na+/H+ exchanger (NHE1)-mediated changes in pHi (HEPES-buffer), and its mechanical counterpart the slow force response (SFR), were evaluated. Furthermore, ROS production in response to a low concentration of Ang II (1.0 nmol/L) or an equipotent concentration of epidermal growth factor (EGF, 0.1 mg/ml) was compared in myocardial tissue slices from both groups. Compared to scramble, animals transduced with l-shMR showed: (1) reduced cardiac MR expression, (2) cancellation of Ang II-induced ROS production but preservation of EGF-induced ROS production, (3) cancellation of stretch-triggered increase in ERK1/2-p90RSK phosphorylation, (4) lack of stretch-induced NHE1 activation, and (5) abolishment of the SFR. Our results provide strong evidence that MR activation occurs after myocardial stretch and is a key factor to promote redox-sensitive kinase activation and their downstream consequences