期刊
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
卷 466, 期 9, 页码 1819-1830出版社
SPRINGER
DOI: 10.1007/s00424-013-1413-y
关键词
Cardiac hypertrophy; Ang II; ET-1; EGFR transactivation; NHE-1; ROS
类别
资金
- Consejo Nacional de Ciencia y Tecnica, Argentina [PIP 1141]
- Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina [PICT 2006-078]
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 similar to 45 % cell surface area (CSA) and similar to 37 % [H-3]-phenylalanine incorporation, effects that were blocked not only by losartan (Los) but also by BQ123 (AT(1) 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 AT(1), 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.
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