The autocrine/paracrine loop after myocardial stretch: Mineralocorticoid receptor activation

ENNIS IL; AIELLO EA; CINGOLANI HE; PÉREZ NG

Current Cardiology Reviews

Bentham Science Publishers

Año: 2013 vol. 9 p. 230 - 240

1573-403X

The stretch of cardiac muscle increases developed force in two phases. The first phase, which occurs rapidly,constitutes the well-known Frank-Starling mechanism and it is generally attributed to enhanced myofilament responsivenessto Ca2+. The second phase or slow force response (SFR) occurs gradually and is due to an increase in the calciumtransient amplitude as a result of a stretch-triggered autocrine/paracrine mechanism. We previously showed that Ca2+ entrythrough reverse Na+/Ca2+ exchange underlies the SFR, as the final step of an autocrine/paracrine cascade involving releaseof angiotensin II/endothelin, and a Na+/H+ exchanger (NHE-1) activation-mediated rise in Na+. In the present reviewwe mainly focus on our three latest contributions to the understanding of this signalling pathway triggered by myocardialstretch: 1) The finding that an increased production of reactive oxygen species (ROS) from mitochondrial origin is criticalin the activation of the NHE-1 and therefore in the genesis of the SFR; 2) the demonstration of a key role played by thetransactivation of the epidermal growth factor receptor; and 3) the involvement of mineralocorticoid receptors (MR) activationin the stretch-triggered cascade leading to the SFR. Among these novel contributions, the critical role played by theMR is perhaps the most important one. This finding may conceivably provide a mechanistic explanation to the recentlydiscovered strikingly beneficial effects of MR antagonism in humans with cardiac hypertrophy and failure.