Signal Transduction Mechanisms Involved in Angiotensin-(1–7)-Stimulated Arachidonic Acid Release and Prostanoid Synthesis in Rabbit Aortic Smooth Muscle Cells

• Published in: The Journal of pharmacology and experimental therapeutics 1998-01, Vol.284 (1), p.388-398
• Main Authors: Muthalif, M M, Benter, I F, Uddin, M R, Harper, J L, Malik, K U
• Format: Article
• Language: English
• Subjects: Angiotensin I; Angiotensin II - pharmacology; Animals; Aorta - metabolism; Arachidonic Acid - secretion; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - physiology; Male; Muscle, Smooth, Vascular - metabolism; Oligonucleotides, Antisense - pharmacology; Peptide Fragments - pharmacology; Phospholipases A - metabolism; Phospholipases A2; Prostaglandins - biosynthesis; Rabbits; Rats; Rats, Sprague-Dawley; Signal Transduction
• ISSN: 0022-3565; 1521-0103

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 [ 3 H]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 [ 3 H]AA release, whereas the AT 2 receptor antagonist PD-123319 inhibited both Ang II- and Ang-(1–7)-induced [ 3 H]AA release. Ang-(1–7) receptor 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 phospholipase A 2 (cPLA 2 ), mitogen-activated protein (MAP) kinase or Ca ++ -/calmodulin-dependent protein (CAM) kinase II antisense oligonucleotides, Ang-(1–7)- and Ang II-induced [ 3 H]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 activity and [ 3 H]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 PLA 2 to the nuclear envelope. These data show that Ang-(1–7) and Ang II stimulate AA release and prostacyclin synthesis via activation of distinct types of AT receptors. 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.