Kanie Noriyasu, Matsumoto Takayuki, Kobayashi Tsuneo, Kamata Katsuo
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Br J Pharmacol. 2003 Sep;140(1):23-32. doi: 10.1038/sj.bjp.0705414. Epub 2003 Jul 29.
(1) The aim of the present study was to investigate the causal relationship between peroxisome proliferator-activated receptor (PPAR) and endothelium-dependent relaxation in streptozotocin (STZ)-induced diabetic rats. (2) Acetylcholine (ACh)-induced endothelium-dependent relaxation was significantly weaker in diabetic rats than in age-matched controls. The decreased relaxation in diabetes was improved by the chronic administration of bezafibrate (30 mg kg-1, p.o., 4 weeks). (3) The expressions of the mRNAs for PPARalpha and PPARgamma were significantly decreased in STZ-induced diabetic rats (compared with the controls) and this decrease was restored partially, but not completely, by the chronic administration of bezafibrate. (4) Superoxide dismutase activity in the aorta was not significantly different between diabetic rats and bezafibrate-treated diabetic rats. (5) 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 nontreated diabetic rats. Although the expression of the mRNA for prepro ET-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. (6) These results suggest that downregulations of PPARalpha and PPARgamma may lead to an increased expression of ppET-1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.
(1) 本研究的目的是探讨过氧化物酶体增殖物激活受体（PPAR）与链脲佐菌素（STZ）诱导的糖尿病大鼠内皮依赖性舒张之间的因果关系。(2) 乙酰胆碱（ACh）诱导的内皮依赖性舒张在糖尿病大鼠中明显弱于年龄匹配的对照组。糖尿病时舒张功能的降低通过长期给予苯扎贝特（30 mg·kg-1，口服，4周）得到改善。(3) STZ诱导的糖尿病大鼠中PPARα和PPARγ的mRNA表达显著降低（与对照组相比），长期给予苯扎贝特可部分但未完全恢复这种降低。(4) 糖尿病大鼠和苯扎贝特治疗的糖尿病大鼠主动脉中的超氧化物歧化酶活性无显著差异。(5) 糖尿病大鼠中NAD(P)H氧化酶p22phox亚基的mRNA表达显著高于对照组，但在苯扎贝特治疗的糖尿病大鼠中低于未治疗的糖尿病大鼠。尽管糖尿病大鼠中前内皮素-1（ppET-1）的mRNA表达明显增加（与对照组相比），但长期给予苯扎贝特可在很大程度上阻止这种增加。(6) 这些结果表明，PPARα和PPARγ的下调可能导致糖尿病状态下ppET-1 mRNA表达增加，这种增加可能引发内皮功能障碍。
