SIGNAL-TRANSDUCTION MECHANISMS INVOLVED IN ANGIOTENSIN-(1-7)-STIMULATED ARACHIDONIC-ACID RELEASE AND PROSTANOID SYNTHESIS IN RABBIT AORTIC SMOOTH-MUSCLE CELLS

This study investigated the signal transduction mechanisms of angioten sin-(1-7) [Ang-(1-7)]- and Ang II-stimulated arachidonic acid (AA) rel ease for prostaglandin (PG) production in rabbit aortic vascular smoot h muscle cells. Ang II and Ang-(1-7) enhanced AA release in cells prel abeled with [H-3]AA. However, 6-keto-PGF(1 alpha) synthesis produced b y Ang II was much less than that caused by Ang-(1-7). In the presence of the lipoxygenase inhibitor baicalein, Ang II enhanced production of 6-keto-PGF(1 alpha) to a greater degree than Ang-(1-7). Angiotensin t ype (AT)(1) receptor antagonist DUP-753 inhibited only Ang II-induced [H-3]AA release, whereas the AT(2) receptor antagonist PD-123319 inhib ited both Ang II- and Ang-(1-7)-induced [H-3]AA release, Ang-(1-7) rec eptor antagonist D-Ala(7)-Ang-(1-7) inhibited the effect of Ang-(1-7), but not of Ang II, In cells transiently transfected with cytosolic ph ospholipase A(2) (cPLA(2)), mitogen-activated protein (MAP) kinase or Ca++-/calmodulin-dependent protein (CAM) kinase II antisense oligonucl eotides, Ang-(1-7)- and Ang II-induced [H-3]AA release was attenuated. The CaM kinase II inhibitor KN-93 and the MAP kinase kinase inhibitor PD-98059 attenuated both Ang-(1-7)- and Ang II-induced cPLA(2) activi ty and [H-3]AA release. Ang-(1-7) and Ang II also increased CaM kinase II and MAP kinase activities. Although KN-93 attenuated MAP kinase ac tivity, PD-98059 did not affect CaM kinase II activity. Both Ang II an d Ang-(1-7) caused translocation of cytosolic PLA(2) to the nuclear en velope. These data show that Ang-(1-7) and Ang II stimulate AA release and prostacyclin synthesis via activation of distinct types of AT rec eptors. Both peptides appear to stimulate CaM kinase II, which in turn , via MAP kinase activation, enhances cPLA(2) activity and release of AA for PG synthesis.