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1 Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: kmalik{at}utmem.edu.
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) that 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 (W-7) and CaMKII (KN-93). cPLA2 inhibitors (pyrrolidine-1), antisense oligonucleotide, and retroviral siRNA also attenuated Ang II-induced Akt phosphorylation. AA increased Akt phosphorylation, and AA metabolism inhibitor 5,8,11,14-eicosatetraynoicacid (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 (CDC) and cytochrome P450 (ketoconazole and 17-ODYA), but not cyclooxygenase (indomethacine), attenuated Ang II- and AA-induced Akt phosphorylation. Furthermore, 5(S)-, 12(S)- and 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 P450 consequent to AA released by CaMKII-activated cPLA2, and independent of H2O2 production.
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