Silencing of NHE-1 blunts the slow force response to myocardial stretch

Néstor G. Pérez, Mariela B. Nolly, Mirian C. Roldan, María C. Villa-Abrille, Eugenio Cingolani, Enrique L. Portiansky, Bernardo V. Álvarez, Irene L. Ennis, Horacio E. Cingolani

Research output: Contribution to journalArticlepeer-review

Abstract

Myocardial stretch induces a biphasic force response: a first abrupt increase followed by a slow force response (SFR), believed to be the in vitro manifestation of the Anrep effect. The SFR is due to an increase in Ca 2+ transient of unclear mechanism. We proposed that Na +/H + exchanger (NHE-1) activation is a key factor in determining the contractile response, but recent reports challenged our findings. We aimed to specifically test the role of the NHE-1 in the SFR. To this purpose small hairpin interference RNA capable of mediating specific NHE-1 knockdown was incorporated into a lentiviral vector (l-shNHE1) and injected into the left ventricular wall of Wistar rats. Injection of a lentiviral vector expressing a nonsilencing sequence (scramble) served as control. Myocardial NHE-1 protein expression and function (the latter evaluated by the recovery of pHi after an acidic load and the SFR) were evaluated. Animals transduced with l-shNHE1 showed reduced NHE-1 expression (45 ± 8% of controls; P < 0.05), and the presence of the lentivirus in the left ventricular myocardium, far from the site of injection, was evidenced by confocal microscopy. These findings correlated with depressed basal pHi recovery after acidosis [ maxdpH i/dt 0.055 ± 0.008 (scramble) vs. 0.009 ± 0.004 (l-shNHE1) pH units/min, P > 0.05], leftward shift of the relationship between J H+ (H + efflux corrected by the intrinsic buffer capacity), and abolishment of SFR (124 ± 2 vs. 101± 2% of rapid phase; P ± 0.05) despite preserved ERK1/2 phosphorylation [247 ± 12 (stretch) and 263 ± 23 (stretch l-shNHE1) % of control; P < 0.05 vs. nonstretched control], wellknown NHE-1 activators. Our results provide strong evidence to propose NHE-1 activation as key factor in determining the SFR to stretch.

Original languageEnglish (US)
Pages (from-to)874-880
Number of pages7
JournalJournal of applied physiology
Volume111
Issue number3
DOIs
StatePublished - Sep 1 2011

Keywords

  • Anrep effect
  • Na /H exchanger
  • SFR

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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