TY - JOUR
T1 - Endogenous endothelin 1 mediates angiotensin II-induced hypertrophy in electrically paced cardiac myocytes through EGFR transactivation, reactive oxygen species and NHE-1
AU - Correa, María V.
AU - Nolly, Mariela B.
AU - Caldiz, Claudia I.
AU - De Cingolani, Gladys E.Chiappe
AU - Cingolani, Horacio E.
AU - Ennis, Irene L.
N1 - Funding Information:
This study was supported in part by grants PIP 1141 from Consejo Nacional de Ciencia y Técnica, Argentina, and PICT 2006–078 from Agencia Nacional de Promoción Científica y Tecnológica, Argentina.
PY - 2014/9
Y1 - 2014/9
N2 - Emerging evidence supports a key role for endothelin-1 (ET-1) and the transactivation of the epidermal growth factor receptor (EGFR) in angiotensin II (Ang II) action. We aim to determine the potential role played by endogenous ET-1, EGFR transactivation and redox-dependent sodium hydrogen exchanger-1 (NHE-1) activation in the hypertrophic response to Ang II of cardiac myocytes. Electrically paced adult cat cardiomyocytes were placed in culture and stimulated with 1 nmol l-1 Ang II or 5 nmol l-1 ET-1. Ang II increased ∼45 % cell surface area (CSA) and ∼37 % [ 3H]-phenylalanine incorporation, effects that were blocked not only by losartan (Los) but also by BQ123 (AT1 and ETA receptor antagonists, respectively). Moreover, Ang II significantly increased ET-1 messenger RNA (mRNA) expression. ET-1 similarly increased myocyte CSA and protein synthesis, actions prevented by the reactive oxygen species scavenger MPG or the NHE-1 inhibitor cariporide (carip). ET-1 increased the phosphorylation of the redox-sensitive ERK1/2-p90RSK kinases, main activators of the NHE-1. This effect was prevented by MPG and the antagonist of EGFR, AG1478. Ang II, ET-1 and EGF increased myocardial superoxide production (187±9 %, 149±8 % and 163.7±6 % of control, respectively) and AG1478 inhibited these effects. Interestingly, Los inhibited only Ang II whilst BQ123 cancelled both Ang II and ET-1 actions, supporting the sequential and unidirectional activation of AT1, ETA and EGFR. Based on the present evidence, we propose that endogenous ET-1 mediates the hypertrophic response to Ang II by a mechanism that involves EGFR transactivation and redox-dependent activation of the ERK1/2-p90RSK and NHE-1 in adult cardiomyocytes.
AB - Emerging evidence supports a key role for endothelin-1 (ET-1) and the transactivation of the epidermal growth factor receptor (EGFR) in angiotensin II (Ang II) action. We aim to determine the potential role played by endogenous ET-1, EGFR transactivation and redox-dependent sodium hydrogen exchanger-1 (NHE-1) activation in the hypertrophic response to Ang II of cardiac myocytes. Electrically paced adult cat cardiomyocytes were placed in culture and stimulated with 1 nmol l-1 Ang II or 5 nmol l-1 ET-1. Ang II increased ∼45 % cell surface area (CSA) and ∼37 % [ 3H]-phenylalanine incorporation, effects that were blocked not only by losartan (Los) but also by BQ123 (AT1 and ETA receptor antagonists, respectively). Moreover, Ang II significantly increased ET-1 messenger RNA (mRNA) expression. ET-1 similarly increased myocyte CSA and protein synthesis, actions prevented by the reactive oxygen species scavenger MPG or the NHE-1 inhibitor cariporide (carip). ET-1 increased the phosphorylation of the redox-sensitive ERK1/2-p90RSK kinases, main activators of the NHE-1. This effect was prevented by MPG and the antagonist of EGFR, AG1478. Ang II, ET-1 and EGF increased myocardial superoxide production (187±9 %, 149±8 % and 163.7±6 % of control, respectively) and AG1478 inhibited these effects. Interestingly, Los inhibited only Ang II whilst BQ123 cancelled both Ang II and ET-1 actions, supporting the sequential and unidirectional activation of AT1, ETA and EGFR. Based on the present evidence, we propose that endogenous ET-1 mediates the hypertrophic response to Ang II by a mechanism that involves EGFR transactivation and redox-dependent activation of the ERK1/2-p90RSK and NHE-1 in adult cardiomyocytes.
KW - Ang II
KW - Cardiac hypertrophy
KW - EGFR transactivation
KW - ET-1
KW - NHE-1
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=84905743832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905743832&partnerID=8YFLogxK
U2 - 10.1007/s00424-013-1413-y
DO - 10.1007/s00424-013-1413-y
M3 - Article
C2 - 24327206
AN - SCOPUS:84905743832
VL - 466
SP - 1819
EP - 1830
JO - Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tiere
JF - Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tiere
SN - 0031-6768
IS - 9
ER -