title: Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors.
abstract: Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO-levels include the vascular renin-angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker l-nitroarginine inhibited AT2 expression. The NO-induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE)-activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57Bl/6 mice an acute i.v. bolus of l-nitroarginine did not change AT2-expression and ACE-activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57Bl/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57Bl/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE-activity.
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany; Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
authors.forename: Vu Thao-Vi
authors.initials: VT
authors.lastname: Dao
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Sawsan
authors.initials: S
authors.lastname: Medini
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Bisha
authors.affiliation: Institute of Transplantation Diagnostics and Cell Therapeutics, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Balz
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Suvorava
authors.affiliation: Otorhinolaryngology Department, University Hospital Rechts der Isar, Munich Technical University, Munich, Germany.
authors.forename: Murat
authors.initials: M
authors.lastname: Bas
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: kojda@uni-duesseldorf.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013552:Swine; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D044139:Receptor, Angiotensin, Type 2; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III
keywords: Angiotensin II type 2 receptor; Angiotensin converting enzyme 1; Endothelial nitric oxide synthase; Exercise; Nitric oxide