title: Endogenous endothelin 1 mediates angiotensin II-induced hypertrophy in electrically paced cardiac myocytes through EGFR transactivation, reactive oxygen species and NHE-1.
abstract: 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 % [(3)H]-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-p90(RSK) 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-p90(RSK) and NHE-1 in adult cardiomyocytes.
authors: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120 S/N, La Plata, 1900, Argentina, mavecorrea@hotmail.com.
authors: María V
authors: MV
authors: Correa
authors: Mariela B
authors: MB
authors: Nolly
authors: Claudia I
authors: CI
authors: Caldiz
authors: Gladys E Chiappe
authors: GE
authors: de Cingolani
authors: Horacio E
authors: HE
authors: Cingolani
authors: Irene L
authors: IL
authors: Ennis
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism*; D002415:Cats; D004195:Disease Models, Animal; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006984:Hypertrophy / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D019332:Endothelin-1; D017382:Reactive Oxygen Species; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D000804:Angiotensin II; D066246:ErbB Receptors