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 Malik

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Abstract

Angiotensin II (Ang II) activates cytosolic phospholipase A 2 (cPLA 2) 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 cPLA 2. 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 cPLA 2 stimulation. Inhibitors of PLD (C 2 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 C 2 ceramide but not by propranolol or RHC 80267. Ang II-induced PLD activation was decreased by the inhibitor methyl arachidonylfiuorophosphate (MAFP) and the antisense oligonucleotide of cPLA 2, 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 cPLA 2 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.

Original languageEnglish (US)
Pages (from-to)623-629
Number of pages7
JournalHypertension
Volume37
Issue number2 II
StatePublished - 2001

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Phospholipase D
Vascular Smooth Muscle
Angiotensin II
Smooth Muscle Myocytes
Phospholipases A
Arachidonic Acid
Phosphatidate Phosphatase
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Lipoxygenase
Lipoprotein Lipase
Ceramides
Mitogen-Activated Protein Kinases
Propranolol
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP4A
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Farnesyltranstransferase
Dilatation and Curettage
Lipoxygenase Inhibitors
Phospholipases

All Science Journal Classification (ASJC) codes

  • Internal Medicine

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20-Hydroxyeicosatetraenoic acid mediates angiotensin II-induced phospholipase D activation in vascular smooth muscle cells. / Parmentier, Jean Hugues; Muthalif, Mubarack M.; Nishimoto, Andrew T.; Malik, Kafait.

In: Hypertension, Vol. 37, No. 2 II, 2001, p. 623-629.

Research output: Contribution to journalArticle

Parmentier, Jean Hugues ; Muthalif, Mubarack M. ; Nishimoto, Andrew T. ; Malik, Kafait. / 20-Hydroxyeicosatetraenoic acid mediates angiotensin II-induced phospholipase D activation in vascular smooth muscle cells. In: Hypertension. 2001 ; Vol. 37, No. 2 II. pp. 623-629.
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AB - Angiotensin II (Ang II) activates cytosolic phospholipase A 2 (cPLA 2) 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 cPLA 2. 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 cPLA 2 stimulation. Inhibitors of PLD (C 2 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 C 2 ceramide but not by propranolol or RHC 80267. Ang II-induced PLD activation was decreased by the inhibitor methyl arachidonylfiuorophosphate (MAFP) and the antisense oligonucleotide of cPLA 2, 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 cPLA 2 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.

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