Abstract

This study investigated the signal transduction mechanisms of angiotensin-(1–7) [Ang-(1–7)]- and Ang II-stimulated arachidonic acid (AA) release for prostaglandin (PG) production in rabbit aortic vascular smooth muscle cells. Ang II and Ang-(1–7) enhanced AA release in cells prelabeled with [³H]AA. However, 6-keto-PGF_1α synthesis produced by 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_1α to a greater degree than Ang-(1–7). Angiotensin type (AT)₁ receptor antagonist DUP-753 inhibited only Ang II-induced [³H]AA release, whereas the AT₂ receptor antagonist PD-123319 inhibited both Ang II- and Ang-(1–7)-induced [³H]AA release. Ang-(1–7) receptor antagonist d-Ala⁷-Ang-(1–7) inhibited the effect of Ang-(1–7), but not of Ang II. In cells transiently transfected with cytosolic phospholipase A₂(cPLA₂), mitogen-activated protein (MAP) kinase or Ca⁺⁺-/calmodulin-dependent protein (CAM) kinase II antisense oligonucleotides, Ang-(1–7)- and Ang II-induced [³H]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 cPLA₂ activity and [³H]AA release. Ang-(1–7) and Ang II also increased CaM kinase II and MAP kinase activities. Although KN-93 attenuated MAP kinase activity, PD-98059 did not affect CaM kinase II activity. Both Ang II and Ang-(1–7) caused translocation of cytosolic PLA₂ to the nuclear envelope. These data show that Ang-(1–7) and Ang II stimulate AA release and prostacyclin synthesisvia activation of distinct types of AT receptors. Both peptides appear to stimulate CaM kinase II, which in turn,via MAP kinase activation, enhances cPLA₂activity and release of AA for PG synthesis.