Klotho gene product may have a role to regulate VEGF and p21 and tightly linked to the endothelial function to release NO
| Project/Area Number |
11670660
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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 |
Circulatory organs internal medicine
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| Research Institution | GUNMA UNIVERSITY |
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Principal Investigator |
NAKAMURA Tetsuya Gunma University, Second Department of Internal Medicine, Lecturer, 医学部, 講師 (10272238)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAI Ryozo Tokyo University, Department of Cardiovascular Medicine, Professor, 循環器内科・教授 (60207975)
KURABAYASHI Masahiko Gunma University, Second Department of Internal Medicine, Professor, 医学部, 教授 (00215047)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Nitric Oxide / Acetylcholine / Aging / Homozygote / Heterozygote |
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| Research Abstract |
A novel murine model of aging (kl/kl mice) was developed by in vivo mutagenesis. We investigated the endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from wild-type (+/+), heterozygous (+/kl) and homozygous (kl/kl) mice for the transgene at age 6 to 9 weeks. The aorta of kl/+ mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) as compared with those of +/+ mice. The reseponse to sodium nitroprusside was unaltered. The contraction to norepinephrine was augmented by treatment with N^G-nitro-L-arginine methyl ester (LNAME) 10^<-5> M, more so in +/+ mice than in kl/+ mice. The treatment with LNAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD.
NO metabolites (NO_2^- and NO_3^-) and cyclic GMP in urine were significantly reduced in kl/+ mice compared with +/+ mice. However, urinary excretion of 6-keto prostaglandin F1α was unaltered. Immunostaining of NO synthase and vascular endothelial growth factor (VEGF) was low and immunostaining of cell cycle-dependent kinase inhibitor p21 was elevated in the aorta of kl/+ mice. No immunostaining of NO synthase was noted in the aorta of kl/kl mice.
Klotho gene product may have a role to regulate VEGF and p21, protect endothelial cells from cellular senescence and tightly linked to the endothelial function to release NO.
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Report
(3 results)
Research Products
(10 results)
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[Publications] Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa, H, Suga T, Matsumura Y, Masuda H, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R.: "Klotho protein protects against endothelial dysfunction"Biochem Biophys Res Commun. 248. 324-329 (1998)
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[Publications] Aizawa H, Saito Y, Nakamura T, Inoue M, Imanari T, Ohyama Y, Matsumura Y, Masuda H, Oba S, Mise N, Kimura K, Hasegawa A, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R.: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats."Biochem Biophys Res Commun. 249. 865-871 (1998)
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[Publications] Ohyama Y, Kurabayashi M, Masuda H, Nakamura T, Aihara Y, Kaname T, Suga T, Arai M, Aizawa H, Matsumura Y, Kuro-o M, Nabeshima Y, Nagai R.: "Molecular cloning of rat klotho cDNA : Markedly decreased expression of klotho by acute inflammatory stress."Biochem Biophys Res Commun. 251. 920-925 (1998)
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