2005 Fiscal Year Final Research Report Summary
EFFECTS OF ATRA AND RETINOIDS ON ENDOTHELIAL FUNCTION
| Project/Area Number |
16590898
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
SUGAWARA Akira TOHOKU UNIVERSITY, HOSPITAL, LECTURER, 病院, 講師 (90270834)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Sadayoshi TOHOKU UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学系研究科, 教授 (40271613)
KANATSUKA Hiroshi TOHOKU UNIVERSITY, HOSPITAL, ASSOCIATE PROFESSOR, 病院・助教授 (80214435)
TAKEUCHI Kazuhisa TOHOKU UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 大学院・医学系研究科, 助教授 (40260426)
KAGECHIKA Hiroyuki TOKYO MEDICAL AND DENTAL UNIVERSITY, SCHOOL OF BIOMEDICAL SCIENCE, PROFESSOR, 大学院・疾患生命科学研究部, 教授 (20177348)
ARIMA Shuji KINKI UNIVERSITY, SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 助教授 (60323010)
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| Project Period (FY) |
2004 – 2005
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| Keywords | retinoic acid / vascular endothelial cells / retinoic acid receptor / retinoid / nitric oxide(NO) / endothelial NO synthase / phosphoinositide 3-kinase |
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| Research Abstract |
Background-A natural retinoid all-trans retinoic acid (ATRA) contains various beneficial effects on vasculatures including suppression of neointima formation after balloon injury. However, little is known regarding ATRA effects on vascular endothelial function. We therefore studied its role in nitric oxide (NO) production of vascular endothelial cells (ECs).
Methods and Results-Human dermal microvascular ECs, human umbilical vein ECs, and SV40-transformed rat lung vascular ECs were incubated with or without ATRA (1μmol/L) for 48 hours. Their NO production was determined using a fluorescent NO indicator diaminofluorescein-2 diacetate. ATRA significantly increased their basal as well as acetylcholine-induced NO production. Treatment with Nω-nitro-L-arginine methyl ester or carboxy-PTIO suppressed their fluorescence. Increase of NO production was also observed by incubation with retinoic acid receptor (RAR) agonist Am580. ATRA-induced NO increase was abolished by co-incubation with RAR ant
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agonist LE540. Moreover, the NO increase was completely inhibited by phosphoinositide 3-kinase (PI3K) inhibitor wortmannin and LY294002. ATRA as well as Am580 enhanced endothelial NO synthase (eNOS) phosphorylation at Ser-1177 as well as Akt phosphorylation at Ser-473 without changing their protein expression. Over-expression of dominant-negative Akt inhibited the eNOS phosphorylation. Moreover, ATRA increased PI3K activity as well as PI3K catalytic subunit p110β protein expression, which was completely inhibited by LE540 treatment. Real-time PCR analyses demonstrated that ATRA increased PI3K catalytic subunit p110β mRNA expression without affecting its stability. Finally, ATRA-induced NO increase was observed in COS-1 cells transfected with wild-type eNOS and RARα, but not with mutated eNOS whose Ser-1177 was substituted.
Conclusions-ATRA increases NO production by eNOS phosphorylation through RAR-mediated PI3K/Akt pathway activation in vascular ECs, and possibly plays beneficial roles in vascular endothelium. Retinoids may therefore be candidates as novel therapeutic agents against vascular disorders with endothelial damages. Less
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[Journal Article] Rosiglitazone protects against cyclosporine-induced pancreatic and renal injury in rats.2005
Author(s)
Chung BH, Li C, Sun BK, Lim SW, Ahn KO, Yang JH, Choi YH, Yoon KH, Sugawara A, Ito S, Kim J, Yang CW
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Journal Title
Am J Transplant. 5
Pages: 1856-1867
Description
「研究成果報告書概要(和文)」より
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