Group VIA phospholipase A2 (iPLA2beta) participates in angiotensin II-induced transcriptional up-regulation of regulator of g-protein signaling-2 in vascular smooth muscle cells.
Rgs2 (regulator of G-protein signaling-2)-deficient mice exhibit severe hypertension, and genetic variations of RGS2 occur in hypertensive patients. RGS2 mRNA up-regulation by angiotensin II (Ang II) in vascular smooth muscle cells (VSMC) is a potentially important negative feedback mechanism in blood pressure homeostasis, but how it occurs is unknown. Here we demonstrate that group VIA phospholipase A2 (iPLA2beta) plays a pivotal role in Ang II-induced RGS2 mRNA up-regulation in VSMC by three independent approaches, including pharmacologic inhibition with a bromoenol lactone suicide substrate, suppression of iPLA2beta expression with antisense oligonucleotides, and genetic deletion in iPLA2beta-null mice. Selective inhibition of iPLA2beta by each of these approaches abolishes Ang II-induced RGS2 mRNA up-regulation. Furthermore, using adenovirus-mediated gene transfer, we demonstrate that restoration of iPLA2beta-expression in iPLA2beta-null VSMC reconstitutes the ability of Ang II to up-regulate RGS2 mRNA expression. In contrast, Ang II-induced vasodilator-stimulated phosphoprotein phosphorylation and Ang II receptor expression are unaffected. Moreover, in wild-type but not iPLA2beta-null VSMC, Ang II stimulates iPLA2 enzymatic activity significantly. Both arachidonic acid and lysophosphatidylcholine, products of iPLA2beta action, induce RGS2 mRNA up-regulation. Inhibition of lipoxygenases, particularly 15-lipoxygenase, and cyclooxygenases, but not cytochrome P450-dependent epoxygenases inhibits Ang II- or AA-induced RGS2 mRNA expression. Moreover, RGS2 protein expression is also up-regulated by Ang II, and this is attenuated by bromoenol lactone. Disruption of the Ang II/iPLA2beta/RGS2 feedback pathway in iPLA2beta-null cells potentiates Ang II-induced vasodilator-stimulated phosphoprotein and Akt phosphorylation in a time-dependent manner. Collectively, our results demonstrate that iPLA2beta participates in Ang II-induced transcriptional up-regulation of RGS2 in VSMC.
Xie
Zhongwen
Z
Department of Physiology and the Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
Gong
Ming C
MC
Su
Wen
W
Turk
John
J
Guo
Zhenheng
Z
D000256:Adenoviridae; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D054522:Group VI Phospholipases A2; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D009281:Naphthalenes / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D054467:Phospholipases A2; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014161:Transduction, Genetic; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008244:Lysophosphatidylcholines; D008840:Microfilament Proteins; D009281:Naphthalenes; D020319:Oligodeoxyribonucleotides, Antisense; D010750:Phosphoproteins; D011753:Pyrones; D020710:RGS Proteins; C514563:RGS2 protein, rat; D012333:RNA, Messenger; C105345:Rgs2 protein, mouse; D014662:Vasoconstrictor Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; D000804:Angiotensin II; D016718:Arachidonic Acid; C068314:6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; D010088:Oxidoreductases; D051057:Proto-Oncogene Proteins c-akt; D010741:Phospholipases A; D054522:Group VI Phospholipases A2; D054467:Phospholipases A2; C516476:Pla2g6 protein, mouse