egf receptor transactivation by endothelin-1 increased chsy-1 mediated by nadph oxidase and phosphorylation of erk1/2

Objective: growth factors [transforming growth factor-β (tgf-β), epidermal growth factor (egf), endothelin-1 (et- 1)] stimulate proteoglycan synthesis resulting in retention and accumulation of low density lipoprotein (ldl) in vessel intima and leading to atherosclerosis development. this study investigated the role of et-1 on the expression of chsy1, proteoglycan synthesizing enzyme, through both egf and tgf-β receptor transactivation in human vascular smooth muscle cells (vsmcs). also, we explored the involvement of nadph oxidase (nox), an important intermediate of redox signaling, in et-1 transactivated egf receptor (egfr) through endothelin receptors. materials and methods: in this experimental study, phosphorylated erk1/2 and chsy1 protein levels in the human vsmcs were measured by western blot analysis using anti phospho-erk1/2 (thr202/tyr204) and anti chsy1 antibodies. results: et-1 (100 nm) and egf (100 ng/ml) stimulated erk1/2 phosphorylation and inhibited in the presence of bosentan (et receptor inhibitor), ag1478 (egfr inhibitor), and dpi (nox antagonist). also, et-1 treatment increased chsy1 enzyme level; this response was suppressed by bosentan, ag1478, dpi, and sb431542, tgf-β receptor antagonist. this study revealed that et-1 increases expression of chsy1 through transactivation of egf and tgf-β receptors. conclusion: transactivation through the egf receptor mediated by phospho-erk1/2 leads to expression of chsy1 protein. egf receptor transactivation by et-1 is shown for the first time, to be dependent on nox enzymes.