Abstract 17589: Klotho Regulates Vascular Endothelial Dysfunction
Objective. Klotho (KL) is a recently discovered anti-aging gene. Genetic mutation of KL expedites the aging process and shortens the lifespan while overexpression of KL slows down the aging process and extends the lifespan by 20%. The objective of this study is to investigate if klotho affects vascular endothelial function.
Methods and Results. The level of plasma KL in KL heterozygeous (+/-) mice is about a half of that of the wild-type mice. Interestingly, vasodilatory responses to acetylcholine and sodium nitroprusside were decreased significantly in KL (+/-) mice, suggesting that klotho deficiency causes vascular endothelial dysfunction. Although the vascular nitric oxide (NO) level is decreased, eNOS protein expression and activity were not altered in KL (+/-) mice, excluding the involvement of eNOS in KL deficiency-induced endothelial dysfunction. Notably, KL deficiency increased vascular superoxide (O2-) production and NADPH oxidase activity. Inhibition of NADPH oxidase activity by apocynin significantly attenuated KL deficiency-induced elevation of blood pressure, suggesting that the upregulation of NADPH oxidase activity is involved in vascular dysfunction. In rat aortic SMCs, overexpression of KL downregulated Nox2 protein expression and O2- production. KL also attenuated angiotensin II-induced superoxide production. Further mechanistic investigation indicated that KL protein increased intracellular cAMP levels and PKA activity. Notably, inhibition of cAMP by Rp-cAMPM eliminated KL-induced upregulation of PKA activity, indicating that the activation of PKA is cAMP-dependent. Interestingly, prevention of the activation of PKA abolished KL-induced downregulation of Nox2 protein expression. Therefore, KL suppressed Nox2 protein expression via the activation of the cAMP-PKA pathway in vascular SMCs.
Conclusion. This study reveals a previously unidentified role of KL in regulating vascular function and Nox2 NADPH oxidase.
- © 2012 by American Heart Association, Inc.