Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen α1(I) gene expression in cardiac fibroblasts

Objective and methods: We have previously demonstrated that mechanical loading of cardiac fibroblasts leads to increased synthesis and gene expression of the extracellular matrix protein collagen. We hypothesised that the upregulation of procollagen gene expression in cardiac fibroblasts, in response to cyclic mechanical load, is mediated by one or more members of the MAP kinase family. To test this hypothesis, the effect of mechanical load on the activation of extracellular signal-regulated kinase (ERK) 1/2, p46/54(JNK), and p38(MAPK) was examined in rat cardiac fibroblasts. Results: Peak phosphorylation of ERK 1/2, p38MAPK kinases, and p46/54(JNK) was observed following 10-20 min of continuous cyclic mechanical load. Mechanical load significantly increased procollagen alpha(1)(l) mRNA levels up to twofold above static controls after 24 h. This increase was completely abolished by the MEK 1/2 inhibitor U0126, with no effect on basal levels. In contrast, SB203580, a specific inhibitor of p38(MAPK), enhanced both basal and stretch-stimulated levels of procollagen mRNA. Consistent with this finding, selective activation of the p38(MAPK) Signalling pathway by expression of MKK6(Glu), a constitutive activator of p38(MAPK), significantly reduced procollagen alpha(1)(l) promoter activity. SB203580-dependent increase in procollagen alpha(1)(l) was accompanied by ERK 1/2 activation, and inhibition of this pathway completely prevented SB203580-induced procollagen alpha(1)(l) expression. Conclusions: These results suggest that mechanical load-induced procollagen alpha(1)(I) gene expression requires ERK 1/2 activation and that the p38(MAPK) pathway negatively regulates gene expression in cardiac fibroblasts. These pathways are likely to be key in events leading to matrix deposition during heart growth and remodelling induced by mechanical load. (C) 2004 European Society of Cardiology. Published by Elsevier B.V All rights reserved.