EFFECTS OF ATRA AND RETINOIDS ON ENDOTHELIAL FUNCTION

• Project/Area Number: 16590898
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: TOHOKU UNIVERSITY
• Principal Investigator: SUGAWARA Akira TOHOKU UNIVERSITY, HOSPITAL, LECTURER, 病院, 講師 (90270834)
• 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)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: retinoic acid / vascular endothelial cells / retinoic acid receptor / retinoid / nitric oxide(NO) / endothelial NO synthase / phosphoinositide 3-kinase / 血管新生 / 動脈硬化

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 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.

Research Products

• [Journal Article] Accelerated Diabetic Nephropathy in Mice Lacking the Peroxisome Proliferator-Activated Receptor {alpha}. (2006)
  • Author(s): Park CW, Kim HW, Ko SH, Chung HW, Lim SW, Yang CW, Chang YS, Sugawara A, Guan Y, Breyer MD
  • Journal Title: Diabetes. 55 Pages: 885-893
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Peroxisome proliferator-activated receptor γ (PPARγ) in human breast carcinoma : a possible modulator of estrogenic actions. (2006)
  • Author(s): Suzuki T, Hayashi S, Miki Y, Ono K, Nakamura Y, Moriya T, Sugawara A, Ishida T, Ohuchi N, Sasano H
  • Journal Title: Endocr Relat Cancer. 13 Pages: 233-250
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor {alpha}. (2006)
  • Author(s): Park CW, Kim HW, Ko SH, Chung HW, Lim SW, Yang CW, Chang YS, Sugawara A, Guan Y, Breyer MD
  • Journal Title: Diabetes. 55 Pages: 885-893
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Peroxisome proliferator-activated receptor γ(PPARγ) in human breast carcinoma : a possible modulator of estrogenic actions. (2006)
  • Author(s): Suzuki T, Hayashi S, Miki Y, Ono K, Nakamura Y, Moriya T, Sugawara A, Ishida T, Ohuchi N, Sasano H
  • Journal Title: Endocr Relat Cancer. 13 Pages: 233-250
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Primary care in the treatment of functional gastrointestinal symptoms in Japan : prescription preferences and impression of results. (2005)
  • Author(s): Hongo M, Kanatsuka H, Sugawara A, Nagasaki Y, Endo Y, Karahashi K, Shoji T, Sagami Y, Aoki I.
  • Journal Title: Aliment Pharmacol Ther. 21 Suppl 2 Pages: 47-54
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Journal Title: Am J Transplant. 5 Pages: 1856-1867
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Up-regulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway. (2005)
  • Author(s): Uruno A, Sugawara A, Kanatsuka H, Kagechika H, Saito A, Sato K, Kudo M, Takeuchi K, Ito S
  • Journal Title: Circulation. 112 Pages: 727-736
  • NAID: 120001182109
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Protective effects of peroxisome proliferators activated receptor gamma agonists on diabetic and non-diabetic renal diseases. (2005)
  • Author(s): Chung BH, Lim SW, Ahn KO, Sugawara A, Ito S, Choi BS, Kim YS, Bang BK, Yang CW
  • Journal Title: Nephrology. 10
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Primary care in the treatment of functional gastrointestinal symptoms in Japan : prescription preferences and impression of results. (2005)
  • Author(s): Hongo M, Kanatsuka H, Sugawara A, Nagasaki Y, Endo Y, Karahashi K, Shoji T, Sagami Y, Aoki I.
  • Journal Title: Aliment Pharmacol Ther. 21 Suppl2 Pages: 47-54
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rosiglitazone protects against cyclosporine-induced pancreatic and renal injury in rats. (2005)
  • Author(s): Chung BH, Li C, Sun BK, Lim SW, AhnKO, Yang JH, Choi YH, Yoon KH, Sugawara A, Ito S, Kim J, Yang CW
  • Journal Title: Am J Transplant. 5 Pages: 1856-1867
• [Journal Article] プロスタサイクリンによる血管内皮細胞でのNO産生亢進作用および血管新生促進作用 (2005)
  • Author(s): 工藤正孝, 菅原 明, 斉藤明子, 宇留野晃, 伊藤貞嘉
  • Journal Title: 血圧 12 Pages: 343-345
• [Journal Article] 脂肪細胞特異的核受容体であるPPARγ2のTNFαによる発現抑制機構:インスリン抵抗性発症要因の分子メカニズムの解明 (2005)
  • Author(s): 工藤正孝, 菅原 明, 宇留野晃, 伊藤貞嘉
  • Journal Title: 血圧 12 Pages: 923-925
• [Journal Article] Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole. (2004)
  • Author(s): Arima S, Kohagura K, Xu HL, Sugawara A, Uruno A, Satoh F, Takeuchi K, Ito S
  • Journal Title: Hypertension. 43[part 2] Pages: 1-6
• [Journal Article] Expression of peroxisome proliferator-activated receptor isoform proteins in the rat kidney. (2004)
  • Author(s): Sato K, Sugawara A, Kudo M, Uruno A, Ito S, Takeuchi K
  • Journal Title: Hypertens Res. 27 Pages: 417-425
  • NAID: 50000009354
• [Journal Article] Transcription suppression of peroxisome proliferator-activated receptor γ2 gene expression by tumor necrosis factor α via an inhibition of CCAAT/enhancer-binding protein δ during the early stage of adipocyte differentiation. (2004)
  • Author(s): Kudo M, Sugawara A, Uruno A, Takeuchi K, Ito S
  • Journal Title: Endocrinology 145 Pages: 4948-4956
• [Journal Article] Decreased expression of retinoid X receptor (RXR) isoforms in human thyroid carcinomas. (2004)
  • Author(s): Takiyama Y, Miyokawa N, Sugawara A, Kato S, Ito K, Sato K, Oikawa K, Kobayashi H, Kimura S, Tateno M
  • Journal Title: J Clin Endocrinol Metab. 89 Pages: 5851-5861
• [Journal Article] HGF stimulates NO production through eNOS phosphorylation by PI3K and MAPK pathways. (2004)
  • Author(s): Uruno A, Sugawara A, Kanatsuka H, Arima S, Taniyama Y, Kudo M, Takeuchi K, Ito S
  • Journal Title: Hypertens Res. 27 Pages: 887-895
• [Journal Article] Nobel RXR antagonists enhance transactivation of PPARg and ST 13 preadipocyte differentiation. (2004)
  • Author(s): Sato M, Sugawara A, Egawa N, Yajima Y, Kato H, Kagechika H
  • Journal Title: 12th Internatinal Congress of Endocrinology International Proceedings. Pages: 547-551
• [Book] シンプル生化学(改訂第5版) (2006)
  • Author(s): 菅原 明
  • Publisher: 南江堂
  • Description: 「研究成果報告書概要(和文)」より