(Verbatim from the application): The peptide hormone angiotensin II (AngII) contributes to various cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The growth promoting activity of the AngII type-1 (AT1) receptor is implicated in the progression of cardiovascular remodeling. In vascular smooth muscle cells (VSMC), AngII is believed to transmit its growth-promoting signal through activation of tyrosine kinases (PYK2, Src, JAK, and EGF receptor). We have reported that the transactivation of the EGF receptor (EGFR) by Angli is essential for the activation of ERK and p70 S6 kinase, and subsequent c-Fos induction and protein synthesis by AngII in cultured VSMC. Thus, the EGFR transactivation could play a central role in AngII mediated vascular remodeling. Several mechanisms implicating an upstream tyrosine kinase, reactive oxygen species (ROS) and a metalloprotease-dependent generation of an EGFR ligand are proposed for the transactivation. However, a huge void remains in our knowledge in terms of the mechanism by which AngII/AT1 activates the EGFR. Also, it is not clear whether other signals such as activation of p38 and JNK MAP kinases by AngII are under control of transactivation, if they are regulated by other tyrosine kinases, or if a tyrosine phosphatase such as SHP-2 is involved. Thus, we will evaluate the hypothesis that the tyrosine kinases (PYK2 and JAK2). the tyrosine phosphatase SHP-2. ROS. and the metalloprotease ADAM regulate activation of EGFR and/or MAP kinases by AngII in VSMC.
The specific aims of this application are 1) to investigate the roles of the following factors in the EGFR transactivation mechanisms by AngII (PYK2, JAK2, ROS, metalloprotease); 2) to investigate the involvement of the tyrosine kinases in activation of p38 and JNK by AnglI; 3) to investigate the role of SHP-2 in regulation of PYK2; 4) to investigate the role of SHP-2 in regulation of MAP kinases by AngII. These studies will unravel the initial key mechanism by which vasculotrophic factors such as Angil regulate vascular remodeling. Moreover, the clarification of the indispensable hypertrophic and hyperplastic signals in combination with the identification of key enzymes (kinases and/or phosphatases) will provide potential therapeutic targets in cardiovascular diseases.
Showing the most recent 10 out of 78 publications
