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Abstract P213: Epidermal Growth Factor Receptor and c-Src Are Involved in Stretch-Induced Activation of JNK1/2 and P38 in Cardiac Myocytes and Cardiac Fibroblasts

Mechanical stretch is a major determinant that leads to heart failure. Heart failure is associated with a steady increase in myocardial angiotensinogen (Ao) expression and the biological peptide angiotensin II (Ang II) formation. We have previously identified key downstream effectors that couple to mechanical stretch-induced Ao gene expression. JNK1/2 and p38α were found to have opposing roles on stretch-induced Ao gene expression in neonatal rat cardiac myocytes (NRVM) and cardiac fibroblasts (NRFB). JNK negatively regulated Ao expression in NRVM and NRFB following acute stretch, whereas with prolonged stretch, p38α was responsible for upregulation of Ao expression. However, the mechanisms leading to activation of these kinases and cross-talk between these signal molecules remain to be determined. Epidermal growth factor receptor (EGFR) is expressed in both NRVM and NRFB, but its precise role in mechanosensing is poorly understood. In NRVM, stretch caused JNK1/2 activation (phosphorylation) within 2 min, with a peak response at 15 min (3.96 ± 0.71 fold, p<0.01). Stretch induced p38 activation within 5 min, which remained elevated (2.93 ± 0.49 fold, p<0.05) at 60 min (final time point). Pretreatment with EGFR blockers AG1478 (100 nM) and BIBX 1382 (200 nM) inhibited stretch-induced activation of JNK at early time points (5 and 15 min), whereas BIBX 1382 and the Ang II receptor type I inhibitor losartan (10 µM) inhibited p38 activation at 60 min. Stretch induced activation of c-Src (phosphorylation of tyrosine 416) at 60 min (1.56 ± 0.21 fold, p<0.01), which was attenuated by losartan. In NRFB, stretch-induce-JNK-phosphorylation can be inhibited by both AG1478 and Src inhibitor PP2 (100 nM) at 15 min. Stretch also increased phosphorylation levels of c-Src at tyrosine 416 and EGFR at tyrosine 1068 at 15 and 60 min, which were blocked in the presence of losartan. In a summary, these studies give strong evidence that both EGFR and c-Src are involved in stretch-induced signal cascade in NRVM and NRFB.