Klotho protein protects against endothelial dysfunction.
Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of klotho mouse or the physiological role of klotho protein as a circulating factor is available. In this report, we demonstrate that 50% effective dose of aortic relaxation in response to acetylcholine in heterozygous klotho mice is significantly greater (4 x 10(-5) M) than in wild-type mice (8 x 10(-6) M, n = 7, p < 0.05) and that the vasodilator response of arterioles to acetylcholine is significantly attenuated in heterozygous (20% effective dose; 2 x 10(-6) M) and homozygous klotho mice (>1 x 10(-5) M) as compared with wild-type mice (1 x 10(-7) M, n = 7, p < 0.05). Nitric oxide metabolites (NO-2 and NO-3) in urine are significantly lower in heterozygous klotho mice (142 +/- 16 nmol/day) than wild-type mice (241 +/- 28 nmol/day, n = 13, p < 0.05). Parabiosis between wild-type and heterozygous klotho mice results in restoration of endothelial function in heterozygous klotho mice. We conclude that the klotho protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.
Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.
Y
Y
Saito
T
T
Yamagishi
T
T
Nakamura
Y
Y
Ohyama
H
H
Aizawa
T
T
Suga
Y
Y
Matsumura
H
H
Masuda
M
M
Kurabayashi
M
M
Kuro-o
Y
Y
Nabeshima
R
R
Nagai
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D005966:Glucuronidase; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D009599:Nitroprusside / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D009599:Nitroprusside; D009569:Nitric Oxide; D005966:Glucuronidase; D000090265:Klotho Proteins; D000109:Acetylcholine