Versatility of the angiotensin II type 1 receptor.

This issue of Circulation Research includes 3 interesting studies that represent new concepts of AT1 receptor–mediated cell signaling in the cardiovascular system, which is currently of intense interest. The AT1 receptor mediates many important cardiovascular responses, including vasoconstriction, vascular and cardiac remodeling (cell proliferation, hypertrophy, and production of extracellular matrix), and cell survival/cell death. The AT1 receptor belongs to the seven membrane–spanning GPCR family and typically activates PLCb through the heterotrimeric Gq protein, causing production of inositol trisphosphate and diacylglycerol. Besides this classical GPCR-Gq-PLCb pathway, recent studies indicate that Ang II activates both nonreceptor-type and receptor-type tyrosine kinases, which are typically activated by cytokine and EGFR stimulation. Activation of tyrosine kinases by Ang II is of great interest for a variety of reasons. First, tyrosine kinase–dependent signaling pathways mediate major growth effects of Ang II in cardiovascular systems. Sayeski et al reports that a 130-kDa protein, which is tyrosine-phosphorylated by Ang II, is identified as p130 and that it potentially works as an effector of Src and PKC in VSMCs. Second, since the AT1 receptor possesses neither intrinsic protein tyrosine kinase activities nor known physical association with tyrosine kinases except interaction with JAK2, the linkage between the AT1 receptor and the tyrosine kinases was unexpected. Murasawa et al reports that Ang II transactivates the EGFR, which in turn mediates DNA synthesis in cardiac fibroblasts. Third, tyrosine kinases mediate activation of small GTP binding proteins (the Ras and Rho family) and downstream MAP kinases. Schmitz et al reports that Ang II activates the aPAK-JNK pathway via a tyrosine kinase–dependent mechanism in VSMCs. Since a comprehensive review on tyrosine kinase activation by Ang II has appeared recently, the focus of this editorial is to highlight findings of the most recent literature, including both cardiovascular and noncardiovascular systems, and the future direction of those new concepts regarding AT1 receptor cell signaling.