The Anrep effect requires transactivation of the epidermal growth factor receptor

交易激励 化学 内分泌学 内科学 阿普辛尼 内皮素1 血管紧张素II 受体 医学 NADPH氧化酶 氧化应激 生物化学 转录因子 基因
作者
María C. Villa‐Abrille,Claudia Irma Caldiz,Irene L. Ennis,Mariela Nolly,María Jesús Casarini,Gladys E. Chiappe de Cingolani,Horacio E. Cingolani,Néstor Gustavo Pérez
出处
期刊:The Journal of Physiology [Wiley]
卷期号:588 (9): 1579-1590 被引量:39
标识
DOI:10.1113/jphysiol.2009.186619
摘要

Myocardial stretch elicits a biphasic contractile response: the Frank–Starling mechanism followed by the slow force response (SFR) or Anrep effect. In this study we hypothesized that the SFR depends on epidermal growth factor receptor (EGFR) transactivation after the myocardial stretch‐induced angiotensin II (Ang II)/endothelin (ET) release. Experiments were performed in isolated cat papillary muscles stretched from 92 to 98% of the length at which maximal twitch force was developed ( L max ). The SFR was 123 ± 1% of the immediate rapid phase ( n = 6, P < 0.05) and was blunted by preventing EGFR transactivation with the Src‐kinase inhibitor PP1 (99 ± 2%, n = 4), matrix metalloproteinase inhibitor MMPI (108 ± 4%, n = 11), the EGFR blocker AG1478 (98 ± 2%, n = 6) or the mitochondrial transition pore blocker clyclosporine (99 ± 3%, n = 6). Stretch increased ERK1/2 phosphorylation by 196 ± 17% of control ( n = 7, P < 0.05), an effect that was prevented by PP1 (124 ± 22%, n = 7) and AG1478 (131 ± 17%, n = 4). In myocardial slices, Ang II (which enhances ET mRNA) or endothelin‐1 (ET‐1)‐induced increase in O 2 − production (146 ± 14%, n = 9, and 191 ± 17%, n = 13, of control, respectively, P < 0.05) was cancelled by AG1478 (94 ± 5%, n = 12, and 98 ± 15%, n = 8, respectively) or PP1 (100 ± 4%, n = 6, and 99 ± 8%, n = 3, respectively). EGF increased O 2 − production by 149 ± 4% of control ( n = 9, P < 0.05), an effect cancelled by inhibiting NADPH oxidase with apocynin (110 ± 6% n = 7), mKATP channels with 5‐hydroxydecanoic acid (5‐HD; 105 ± 5%, n = 8), the respiratory chain with rotenone (110 ± 7%, n = 7) or the mitochondrial permeability transition pore with cyclosporine (111 ± 10%, n = 6). EGF increased ERK1/2 phosphorylation (136 ± 8% of control, n = 9, P < 0.05), which was blunted by 5‐HD (97 ± 5%, n = 4), suggesting that ERK1/2 activation is downstream of mitochondrial oxidative stress. Finally, stretch increased Ser703 Na + /H + exchanger‐1 (NHE‐1) phosphorylation by 172 ± 24% of control ( n = 4, P < 0.05), an effect that was cancelled by AG1478 (94 ± 17%, n = 4). In conclusion, our data show for the first time that EGFR transactivation is crucial in the chain of events leading to the Anrep effect.
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