In vivo key role of reactive oxygen species and NHE-1 activation in determining excessive cardiac hypertrophy

CINGOLANI OH; PÉREZ NG; ENNIS IL; ALVAREZ, MC; MOSCA, SM; SCHINELLA GR; CÓNSOLE G; CINGOLANI HE

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY

SPRINGER

Año: 2011 vol. 462 p. 733 - 743

0031-6768

Growing in vitro evidence suggests NHE-1, known target for reactive oxygen species(ROS), as mediator of cardiac hypertrophy (CH). Moreover, NHE-1 inhibition was showneffective in preventing CH and failure; so has been the case for AT1 receptor (AT1R)blockers. Previous experiments indicate that myocardial stretch promotes angiotensin IIrelease and post-translational NHE-1 activation, however; in vivo data supporting thismechanism is scanty. In this work we thought to provide in vivo evidence linking AT1Rwith ROS and NHE-1 activation in mediating maladaptive CH. CH was induced in miceby transverse aortic constriction (TAC). A group of animals was treated with the AT1Rblocker losartan. Cardiac contractility was assessed by echocardiography and pressurevolumeloop hemodynamics. After 7 weeks, TAC increased left ventricular (LV) mass by~45% vs.sham and deteriorated LV systolic function. CH was accompanied by activationof the redox-sensitive kinase p90RSK with the consequent increase in NHE-1phosphorylation. Losartan prevented p90RSK and NHE-1 phosphorylation, amelioratedCH and restored cardiac function despite decreased LV wall thickness and similar LVsystolic pressures and diastolic dimensions (increased LV wall stress). In conclusion,AT1R blockade prevented excessive oxidative stress, p90RSK and NHE-1phosphorylation, and decreased CH through a direct action independently ofhemodynamic changes. In addition, cardiac performance improved despite higher workload.