Myocardial mineralocorticoid receptor activation by stretching and its functional consequences

Romina G. Díaz, Néstor G. Pérez, Patricio E. Morgan, María C. Villa-Abrille, Claudia I. Caldiz, Mariela B. Nolly, Enrique L. Portiansky, Irene L. Ennis, Horacio E. Cingolani

Research output: Contribution to journalArticlepeer-review

Abstract

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 of pharmacological MR blockers. Small hairpin interference RNA capable of specifically knocking down 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 nonsilencing 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-p90), the consequent Na/H exchanger-mediated changes in pHi (HEPES-buffer), and its mechanical counterpart, the slow force response, were evaluated. Furthermore, reactive oxygen species production in response to a low concentration of angiotensin II (1.0 nmol/L) or an equipotent concentration of epidermal growth factor (0.1 μg/mL) was compared in myocardial tissue slices from both groups. Compared with scramble, animals transduced with l-shMR showed (1) reduced cardiac MR expression, (2) cancellation of angiotensin II-induced reactive oxygen species production but preservation of epidermal growth factor-induced reactive oxygen species production, (3) cancellation of stretch-triggered increase in ERK1/2-p90 phosphorylation, (4) lack of stretch-induced Na/H exchanger activation, and (5) abolishment of the slow force response. 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.

Original languageEnglish (US)
Pages (from-to)112-118
Number of pages7
JournalHypertension
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2014

Keywords

  • Mineralocorticoid receptors
  • Myocardial stretch
  • Na+/H+ exchanger

ASJC Scopus subject areas

  • Internal Medicine

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