CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
Myocardial Mineralocorticoid Receptor Activation by Stretching and Its Functional Consequences
DÍAZ RG; PEREZ NG; MORGAN PE; VILLA ABRILLE MC; CALDIZ CI; NOLLY M, ; PORTIANSKY EL; ENNIS IL; CINGOLANI HE
LIPPINCOTT WILLIAMS & WILKINS
Lugar: Philadelphia; Año: 2014 vol. 63 p. 112 - 118
Myocardial stretch triggers an angiotensin II?dependent autocrine/paracrine loop of intracellular signals,leading to reactive oxygen species?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 ofpharmacological MR blockers. Small hairpin interference RNA capable of specifically knocking down the MR wasincorporated into a lentiviral vector (l-shMR) and injected into the left ventricular wall of Wistar rats. The samevector but expressing a nonsilencing sequence (scramble) was used as control. Lentivirus propagation through the leftventricle was evidenced by confocal microscopy. Myocardial MR expression, stretch-triggered activation of redoxsensitivekinases (ERK1/2-p90RSK), the consequent Na+/H+ exchanger?mediated changes in pHi (HEPES-buffer), andits mechanical counterpart, the slow force response, were evaluated. Furthermore, reactive oxygen species productionin response to a low concentration of angiotensin II (1.0 nmol/L) or an equipotent concentration of epidermal growthfactor (0.1 μg/mL) was compared in myocardial tissue slices from both groups. Compared with scramble, animalstransduced with l-shMR showed (1) reduced cardiac MR expression, (2) cancellation of angiotensin II?induced reactiveoxygen species production but preservation of epidermal growth factor?induced reactive oxygen species production,(3) cancellation of stretch-triggered increase in ERK1/2-p90RSK phosphorylation, (4) lack of stretch-induced Na+/H+exchanger activation, and (5) abolishment of the slow force response. Our results provide strong evidence that MRactivation occurs after myocardial stretch and is a key factor to promote redox-sensitive kinase activation and theirdownstream consequences.