| 20231142 |
Villa-Abrille MC, Caldiz CI, Ennis IL, Nolly MB, Casarini MJ, Chiappe de Cingolani GE, Cingolani HE, Perez NG: The Anrep effect requires transactivation of the epidermal growth factor receptor. J Physiol. 2010 Mar 15.
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 Ang II/ET release. Experiments were performed in isolated cat papillary muscles stretched from 92 to 98% of Lmax. The SFR was 123+/-1% of rapid phase (n=6, P <0.05) and was blunted by preventing EGFR transactivation with the Src-kinase inhibitor (PP1, 99+/-2%, n=4), the matrix metalloproteinase inhibitor (MMPI, 8+/-4%, n=11), by EGFR blockade (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), effect that was prevented by PPI (124+/-22%, n=7) and AG1478 (131+/-17%, n=4). In myocardial slices, Ang II (that enhance ET mRNA) or ET-1-induced increase in O2- 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 O2- production by 149+/-4% of control (n=9, P <0.05), effect canceled by inhibiting NADPH oxidase (apocynin, 110+/-6% n=7), mKATP channels (5-HD, 105+/-5%, n=8), respiratory chain (rotenone, 110+/-7%, n=7) or MPTP (Cyclosporine, 111+/-10%, n=6). EGF increased ERK1/2 phosphorylation (136+/-8% of control, n=9, P <0.05), that was blunted by 5-HD (97+/-5%, n=4) suggesting that ERK 1/2 activation is downstream mitochondrial oxidative stress. Finally, stretch increased Ser703 NHE-1 phosphorylation by 172+/-24% of control (n=4, P <0.05), 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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