INVESTIGADORES
ENNIS Irene Lucia
artículos
Título:
Aldosterone Stimulates the Cardiac Na+/H+ Exchanger via Transactivation of the Epidermal Growth Factor Receptor
Autor/es:
DE GIUSTI VC; NOLLY MB; YEVES AM; CALDIZ CB; VILLA-ABRILLE MCM; CHIAPPE DE CINGOLANI GE; ENNIS IL; CINGOLANI HE; AIELLO EA
Revista:
HYPERTENSION
Editorial:
LIPPINCOTT WILLIAMS & WILKINS
Referencias:
Año: 2011 vol. 58 p. 912 - 919
ISSN:
0194-911X
Resumen:
The use of antagonists of the mineralocorticoid receptor in the
treatment of myocardial hypertrophy and heart failure has gained
increasing importance in the last years. The cardiac Na(+)/H(+)
exchanger (NHE-1) upregulation induced by aldosterone could account for
the genesis of these pathologies. We tested whether aldosterone-induced
NHE-1 stimulation involves the transactivation of the epidermal growth
factor receptor (EGFR). Rat ventricular myocytes were used to measure
intracellular pH with epifluorescence. Aldosterone enhanced the NHE-1
activity. This effect was canceled by spironolactone or eplerenone
(mineralocorticoid receptor antagonists), but not by mifepristone
(glucocorticoid receptor antagonist) or cycloheximide (protein synthesis
inhibitor), indicating that the mechanism is mediated by the
mineralocorticoid receptor triggering nongenomic pathways.
Aldosterone-induced NHE-1 stimulation was abolished by the EGFR kinase
inhibitor AG1478, suggesting that is mediated by transactivation of
EGFR. The increase in the phosphorylation level of the kinase p90(RSK)
and NHE-1 serine703 induced by aldosterone was also blocked by AG1478.
Exogenous epidermal growth factor mimicked the effects of aldosterone on
NHE-1 activity. Epidermal growth factor was also able to increase
reactive oxygen species production, and the epidermal growth
factor-induced activation of the NHE-1 was abrogated by the reactive
oxygen species scavenger N-2-mercaptopropionyl glycine, indicating that
reactive oxygen species are participating as signaling molecules in this
mechanism. Aldosterone enhances the NHE-1 activity via transactivation
of the EGFR, formation of reactive oxygen species, and phosphorylation
of the exchanger. These results call attention to the consideration of
the EGFR as a new potential therapeutic target of the cardiovascular
pathologies involving the participation of aldosterone.