2003 Fiscal Year Final Research Report Summary
Adipocytokine-related genes and insulin resistance
| Project/Area Number |
14570090
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General pharmacology
|
|---|
| Research Institution | Hoshi University |
|---|
Principal Investigator |
KAMATA Katsuo Hoshi University, Inst. Med. Chem., Professor, 医薬品化学研究所, 教授 (40121496)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Takayuki Hoshi University, Inst. Med. Chem., Research Assistant, 医薬品化学研究所, 助手 (30366835)
KOBAYASHI Tsuneo Hoshi University, Inst. Med. Chem., Research Assistant, 医薬品化学研究所, 助手 (90339523)
|
|---|
| Project Period (FY) |
2002 – 2003
|
| Keywords | adipocytokine / diabetes mellitus / endothelium / endothelin-1 / NAD / Hoxidase / PPARα / EDHF / cyclic AMP |
|---|
| Research Abstract |
1) We tested J-104132, a potent orally active mixed antagonist of endothelin A and B (ET_A/ET_B) receptors in streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. The acetyicholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was significantly attenuated following chronic administration of J-104132. The amount of superoxide anion was significantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment significantly decreased the level of superoxide anion in diabetic rats. The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was significantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.
2) The decreased rela
… More
xation in diabetes was improved by the chronic administration of bezafibrate. The expressions of the mRNAs for PPARx and PPARγ were significantly decreased in STZ-induced diabetic ratsand this decrease was restored partially, but not completely, by the chronic administration of bezafibrate. The expression of the mRNA for the p22phox subunit of NAD(P)H oxidase was significantly higher in diabetics than in controls, but it was lower in bezafibrate-treated diabetic rats than in non-treated diabetic rats. Although the expression of the mRNA for preproET-1 (ppET-1) was markedly increased in diabetic rats (compared with controls), this increase was prevented to a significant extent by the chronic administration of bezafibrate. These results suggest that downregulations of PPARct and y may lead to an increased expression of prepro ET-1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.
3) In isolated superior mesenteric artery rings from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHF-type relaxation was significantly weaker in STZ-induced diabetic rats, and enhanced by 3-isobutyl-1-methylxanthine, a cAMP-phosphodiesterase inhibitor. These enhanced EDKF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHE-type relaxation was enhanced by cilostamide, a phosphodiesterase 3 (PDE3)-selective inhibitor, but not by Ro 20-1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP phosphodiesterases (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but that for PDE4D was not We conclude that the impairment of EDHE-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity.
4) In adiponectin knockout mice, acetylcholine-induced relaxation was not changed as compared with controls, indicating that the reduced adiponectin itself induces the vascular complications. Less
|
Research Products
(15 results)
