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(Hypertension. 2001;37:623.)
© 2001 American Heart Association, Inc.

Scientific Contributions

20-Hydroxyeicosatetraenoic Acid Mediates Angiotensin II–Induced Phospholipase D Activation in Vascular Smooth Muscle Cells

Jean-Hugues Parmentier; Mubarack M. Muthalif; Andrew T. Nishimoto; Kafait U. Malik

From the Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tenn.

Correspondence to Kafait U. Malik, PhD, DSc, Professor of Pharmacology, College of Medicine, The University of Tennessee at Memphis, 874 Union Avenue, Memphis, TN 38163. E-mail kmalik{at}utmem.edu

Angiotensin II (Ang II) activates cytosolic phospholipase A₂ (cPLA₂) and phospholipase D (PLD) in rabbit vascular smooth muscle cells (VSMCs). Ang II also activates ras/mitogen-activated protein (MAP) kinase in VSMCs; this activation is mediated by 20-hydroxyeicosatetraenoic acid (HETE) and 12(S)-HETE, which are metabolites of arachidonic acid generated by cytochrome P450 4A and lipoxygenase, respectively, produced on activation of cPLA₂. The purpose of this study was to determine if Ang II–induced PLD activation in VSMCs is mediated through the ras/extracellular signal-regulating kinase (ERK) pathway by arachidonic acid metabolites that are generated consequent to cPLA₂ stimulation. Inhibitors of PLD (C₂ ceramide), phosphatidate phosphohydrolase (propranolol), and diacylglycerol lipase (RHC 80267) attenuated Ang II–induced arachidonic acid release. Ang II–induced PLD activation, as measured by [³H]phosphatidylethanol production, was inhibited by C₂ ceramide but not by propranolol or RHC 80267. Ang II–induced PLD activation was decreased by the inhibitor methyl arachidonylfluorophosphate (MAFP) and the antisense oligonucleotide of cPLA₂. Inhibitors of lipoxygenases (baicalein) and cytochrome P450 4A (ODYA) attenuated Ang II–induced PLD activation. 20-HETE and 12(S)-HETE increased PLD activity. Inhibitors of ras farnesyltransferase (FPT III and BMS-191563) and MAP kinase kinase (UO126) attenuated the increase in PLD activity elicited by 20-HETE and Ang II. PLD2 was the main isoform activated by Ang II in VSMCs. These data suggest that the CYP4A metabolite 20-HETE, which is generated from arachidonic acid after cPLA₂ activation by Ang II, stimulates the ras/MAP kinase pathway, which in turn activates PLD2 and releases further arachidonic acid for prostaglandin synthesis through the phosphatidate phosphohydrolase/diacylglycerol lipase pathway.

Key Words: phospholipases • angiotensin • cytochrome • muscle, smooth, vascular • arachidonic acid • 20-HETE

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