Production of nitric oxide, but not prostacyclin, is reduced in klotho mice.
A novel murine model of aging (kl/kl mice) has been developed by in vivo mutagenesis. We analyzed endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from 6- to 9-week old wild-type (+/+) and heterozygous (kl/+) klotho mice. The aortas of kl/+ mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) compared to +/+ mice. The response to sodium nitroprusside was unaltered in kl/+ mice. The contraction in response to norepinephrine was augmented by treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-5) M) to a greater extent in +/+ mice than in kl/+ mice. Treatment with L-NAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD. NO metabolites (NO2- and NO3-) and cGMP concentrations in the urine were significantly reduced in kl/+ mice compared to +/+ mice. However, the urinary excretion of 6-keto-prostaglandin F1alpha was unaltered. There was little immunostaining for NO synthase and vascular endothelial growth factor (VEGF) in the aorta of kl/+ mice. No immunostaining for NO synthase was noted in the aorta of kl/kl mice. The expression of the klotho gene product may have a role in the regulation of VEGF expression and is tightly linked to endothelial release of NO.
The Second Department of Internal Medicine, Gunma University School of Medicine, Maebaeshi, Japan. nakamurt@showa.gunma-u.ac.jp
Tetsuya
T
Nakamura
Yuichiro
Y
Saito
Yoshio
Y
Ohyama
Hiroaki
H
Masuda
Hiroyuki
H
Sumino
Makoto
M
Kuro-o
Youichi
Y
Nabeshima
Ryozo
R
Nagai
Masahiko
M
Kurabayashi
D000818:Animals; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D005966:Glucuronidase; D006579:Heterozygote; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009569:Nitric Oxide; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins; D019331:NG-Nitroarginine Methyl Ester