Implication of c‐Src Tyrosine Kinase in Angiotensin II and Endothelin‐1‐induced MAPK Activation and Early Growth‐Response Factor‐1 Expression in Vascular Smooth Muscle Cells (VSMC)

Aberration in endothelin‐1 (ET‐1) and angiotensin II (Ang II) signaling is thought to contribute to the development of vascular pathologies such as hypertension and atherosclerosis. This occurs through the hyperactivation of growth promoting signal transduction pathways, including PI3K/PKB and the MAPK pathways, and regulation of transcription factors, such as early growth response factor‐1 (egr‐1), which was recently shown to be expressed in atherosclerotic plaque. We have previously shown that c‐Src, a non‐receptor protein tyrosine kinases (NR‐PTK), is an upstream regulator of ET‐1 and Ang II‐induced activation of PKB in VSMC. However, the role of c‐Src in ET‐1‐induced MAPK signaling remains controversial in VSMC. Therefore, in the present studies, we have investigated the involvement of c‐Src in ET‐1 and Ang II‐induced MAPK activation and egr‐1 regulation. ET‐1 and Ang II induced the phosphorylation of MAPKs, and enhanced the expression of egr‐1 in VSMC, which was decreased by PP2, a Src inhibitor. Furthermore, knockdown of c‐Src by siRNA also exhibited a similar response, and inhibited ET‐1 and Ang II‐induced MAPK phosphorylation and egr‐1 expression. In summary, these data demonstrate that both ET‐1 and Ang II signal the activation of MAPKs and egr‐1 expression through a c‐Src dependent mechanism in VSMC. (Supported by grants from CIHR)