The direct antioxidative and anti-inflammatory effects of peroxisome proliferator-activated receptors ligands are associated with the inhibition of angiotensin converting enzyme expression in streptozotocin-induced diabetic rat aorta.
Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.
Toba
Hiroe
H
Department of Clinical Pharmacology, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan. toba@mb.kyoto-phu.ac.jp
Miki
Shunsuke
S
Shimizu
Takahiro
T
Yoshimura
Akiko
A
Inoue
Riyako
R
Sawai
Naoki
N
Tsukamoto
Rie
R
Murakami
Masahumi
M
Morita
Yosuke
Y
Nakayama
Yusuke
Y
Kobara
Miyuki
M
Nakata
Tetsuo
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D001629:Bezafibrate / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression / Q000235:genetics; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D045162:Thiazolidinediones; D019010:Vascular Cell Adhesion Molecule-1; D053495:Osteopontin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D007703:Peptidyl-Dipeptidase A; D000077205:Pioglitazone; D001629:Bezafibrate