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CELLULAR AND MOLECULAR

Angiotensin II-Induced Akt Activation through the Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells Is Mediated by Phospholipid Metabolites Derived by Activation of Phospholipase D

Department of Pharmacology and Vascular Biology Center of Excellence, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee

Angiotensin II (Ang II) activates cytosolic Ca²⁺-dependent phospholipase A₂ (cPLA₂), phospholipase D (PLD), p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR) and Akt in vascular smooth muscle cells (VSMC). This study was conducted to investigate the relationship between Akt activation by Ang II and other signaling molecules in rat VSMC. Ang II-induced Akt phosphorylation was significantly reduced by the PLD inhibitor 1-butanol, but not by its inactive analog 2-butanol, and by brefeldin A, an inhibitor of the PLD cofactor ADP-ribosylation factor, and in cells infected with retrovirus containing PLD₂ siRNA or transfected with PLD₂ antisense but not control LacZ or sense oligonucleotide. Diacylglycerol kinase inhibitor II diminished Ang II-induced and diC8-phosphatidic acid (PA)-increased Akt phosphorylation, suggesting that PLD-dependent Akt activation is mediated by PA. Ang II-induced EGFR phosphorylation was inhibited by 1-butanol and PLD₂ siRNA and also by cPLA₂ siRNA. In addition, the inhibitor of arachidonic acid (AA) metabolism 5,8,11,14-eicosatetraynoic acid (ETYA) reduced both Ang II- and AA-induced EGFR transactivation. Furthermore, ETYA, cPLA₂ antisense, and cPLA₂ siRNA attenuated Ang II-elicited PLD activation. p38 MAPK inhibitor SB202190 [4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] reduced PLD activity and EGFR and Akt phosphorylation elicited by Ang II. Pyrrolidine-1, a cPLA₂ inhibitor, and cPLA₂ siRNA decreased p38 MAPK activity. These data indicate that Ang II-stimulated Akt activity is mediated by cPLA₂-dependent, p38 MAPK regulated PLD₂ activation and EGFR transactivation. We propose the following scheme of the sequence of events leading to activation of Akt in VSMC by Ang II: Ang IIcPLA₂AAp38 MAPKPLD₂PAEGFRAkt.

Address correspondence to: Dr. Kafait U. Malik, Professor of Pharmacology, Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Room 115, Crowe Building, 874 Union Avenue, Memphis, TN 38163. E-mail: kmalik{at}utmem.edu

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