Endothelial monocyte-activating polypeptide II causes NOS-dependent pulmonary artery vasodilation: a novel effect for a proinflammatory cytokine.
Endothelial monocyte-activating polypeptide (EMAP) II is a novel proinflammatory cytokine that is released from apoptotic and hypoxic cells. The purpose of this study was to determine the effect of EMAP II on the pulmonary artery (PA) and to characterize its mechanism of action. To study this, isolated PA rings from adult male Sprague-Dawley rats were suspended on steel hooks connected to force transducers and immersed in 37 degrees C organ baths containing modified Krebs-Henseleit solution. After equilibration, force displacement of phenylephrine-preconstricted PA was measured in response to EMAP II. Experiments were performed in endothelium-intact rings, endothelium-denuded rings, and in the presence of the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). Pulmonary artery rings were then subjected to quantitative PCR analysis for inducible NOS (iNOS) mRNA. EMAP II caused a maximal vasodilation of 251 +/- 30.7 mg in endothelium-intact PA. EMAP II caused no vasodilation in endothelium-denuded and l-NAME-treated PA (20 +/- 14.0 mg and 17.5 +/- 7.5 mg, respectively, P < 0.001 vs. endothelium intact). In addition to its vasoactive properties, EMAP II increased PA iNOS mRNA twofold compared with controls. These results demonstrate that 1) EMAP II causes PA vasodilation; 2) EMAP II-mediated PA vasodilation is endothelium dependent and NOS dependent; and 3) EMAP II upregulates iNOS mRNA expression in PA. This report constitutes the first demonstration of EMAP II's effects on the pulmonary artery, its mechanism of action, and represents the identification of the first proinflammatory cytokine to cause PA vasodilation.
Tsai
Ben M
BM
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Wang
Meijing
M
Clauss
Matthias
M
Sun
Peichuan
P
Meldrum
Daniel R
DR
D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011651:Pulmonary Artery / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester