3-hydroxy-3-methylglutaryl-CoA reductase inhibitors block calcium-dependent tyrosine kinase Pyk2 activation by angiotensin II in vascular endothelialcells - Involvement of geranylgeranylation of small G protein Rap1

We recently reported the calcium-dependent activation of tyrosine kinase Py k2 by angiotensin II (Ang II) in pulmonary vein endothelial cells (PVEC). S ince Pyk2 has no calcium binding domain, and neither Ca2+ nor Ca2+/calmodul in directly activates Pyk2, it is not clear how Ca2+ transduces the signal to activate Pyk2, a key tyrosine kinase, in the early events of Ang II sign aling. In the present study, we investigated the mechanism of the calcium-d ependent activation of Pyk2 in response to Ang II by using 3-hydroxy-3-meth ylglutaryl-CoA reductase inhibitors and isoprenoid intermediates in PVEC, W e have obtained substantial evidence indicating that Ang II activates Pyk2 through calcium-mediated activation of the geranylgeranylated small G prote in Rap1 and the Rap1 association with Pyk2. Thus, the small G protein Rap1 is an intermediary signaling molecule linking Ang II-induced calcium signal to Pyk2 activation in PVEC. In addition, our results indicate that 3-hydro xy-3-methylglutaryl-CoA reductase inhibitors, a class of cholesterol-loweri ng drugs, could interrupt Ang II signaling independent of cholesterol lower ing in endothelial cells.