HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 288/5/H2306    most recent 00571.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Li, F. Articles by Malik, K. U. Search for Related Content PubMed PubMed Citation Articles by Li, F. Articles by Malik, K. U.

Angiotensin II-induced Akt activation is mediated by metabolites of arachidonic acid generated by CaMKII-stimulated Ca²⁺-dependent phospholipase A₂

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee

Angiotensin II (ANG II) promotes vascular smooth muscle cell (VSMC) growth, stimulates Ca²⁺-calmodulin (CaM)-dependent kinase II (CaMKII), and activates cytosolic Ca²⁺-dependent phospholipase A₂ (cPLA₂), which releases arachidonic acid (AA). ANG II also generates H₂O₂ and activates Akt, which have been implicated in ANG II actions in VSMC. This study was conducted to investigate the relationship of these signaling molecules to Akt activation in rat aortic VSMC. ANG II increased Akt activity, as measured by its phosphorylation at serine-473. ANG II (200 nM)-induced Akt phosphorylation was decreased by extracellular Ca²⁺ depletion and calcium chelator EGTA and inhibitors of CaM [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide] and CaMKII {(2-[N-(2-hydroxyethyl)]-N-(4-me-thoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzyl-amine)}. cPLA₂ inhibitor pyrrolidine-1, antisense oligonucleotide, and retroviral small interfering RNA also attenuated ANG II-induced Akt phosphorylation. AA increased Akt phosphorylation, and AA metabolism inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) blocked ANG II- and AA-induced Akt phosphorylation (199.03 ± 27.91% with ANG II and 110.18 ± 22.40% with ETYA + ANG II; 405.00 ± 86.22% with AA and 153.97 ± 63.26% with ETYA + AA). Inhibitors of lipoxygenase (cinnamyl-3,4-dihydroxy--cyanocinnamate) and cytochrome P-450 (ketoconazole and 17-octadecynoic acid), but not cyclooxygenase (indomethacin), attenuated ANG II- and AA-induced Akt phosphorylation. Furthermore, 5(S)-, 12(S)-, 15(S)-, and 20-hydroxyeicosatetraenoic acids and 5,6-, 11,12-, and 14,15-epoxyeicosatrienoic acids increased Akt phosphorylation. Catalase inhibited ANG II-increased H₂O₂ production but not Akt phosphorylation. Oleic acid, which also increased H₂O₂ production, did not cause Akt phosphorylation. These data suggest that ANG II-induced Akt activation in VSMC is mediated by AA metabolites, most likely generated via lipoxygenase and cytochrome P-450 consequent to AA released by CaMKII-activated cPLA₂ and independent of H₂O₂ production.

angiotensin II; Akt; hydroxyeicosatetraenoic acids; lipoxygenase; Ca²⁺-dependent phospholipase A₂; epoxyeicosatrienoic acid; reactive oxygen species

This article has been cited by other articles:

				S.-Y. Kim, R. Gul, S.-Y. Rah, S. H. Kim, S. K. Park, M.-J. Im, H. J. Kwon, and U.-H. Kim Molecular mechanism of ADP-ribosyl cyclase activation in angiotensin II signaling in murine mesangial cells Am J Physiol Renal Physiol, April 1, 2008; 294(4): F982 - F989. [Abstract] [Full Text] [PDF]

				S. J. Khundmiri, M. A. Metzler, M. Ameen, V. Amin, M. J. Rane, and N. A. Delamere Ouabain induces cell proliferation through calcium-dependent phosphorylation of Akt (protein kinase B) in opossum kidney proximal tubule cells Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1247 - C1257. [Abstract] [Full Text] [PDF]

				J. H. Lee and L. Ragolia AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1355 - C1365. [Abstract] [Full Text] [PDF]

				M. K. Middleton, A. M. Zukas, T. Rubinstein, M. Jacob, P. Zhu, L. Zhao, I. Blair, and E. Pure Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease J. Exp. Med., October 30, 2006; 203(11): 2529 - 2540. [Abstract] [Full Text] [PDF]

				J.-H. Parmentier, Z. Pavicevic, and K. U. Malik ANG II stimulates phospholipase D through PKC{zeta} activation in VSMC: implications in adhesion, spreading, and hypertrophy Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H46 - H54. [Abstract] [Full Text] [PDF]

				F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2592 - H2601. [Abstract] [Full Text] [PDF]

				T. Endoh Involvement of Src tyrosine kinase and mitogen-activated protein kinase in the facilitation of calcium channels in rat nucleus of the tractus solitarius by angiotensin II J. Physiol., November 1, 2005; 568(3): 851 - 856. [Abstract] [Full Text] [PDF]