Abstract 14290: Genetic Deficiency of Anti-aging Gene Klotho Impairs Vascular Endothelial Function and Causes Arterial Stiffening
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 and arterial compliance.
Methods and Results: Plasma KL in KL mutant heterozygeous (+/-) mice is about a half of that of the wild-type mice while plasma KL in KL mutant homozygeous (-/-) mice is nearly zero. Vasodilatory responses to acetylcholine and sodium nitroprusside were decreased significantly while pulse wave velocity (PWV) was increased in KL (+/-) mice, suggesting that klotho deficiency causes vascular endothelial dysfunction and arterial stiffening. 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 and arterial stiffening. KL deficiency increased vascular superoxide (O2-) production and NADPH oxidase activity which may be involved in vascular endothelial dysfunction. Histological examination showed a significant decrease in aortic elastin content in KL(-/-) mice. Alizarin red staining indicated a significant increase in calcium deposit in aortic walls in KL(-/-) mice, indicating that KL deficiency causes vascular calcification. Interestingly, expression of MMP2, BMP2, RUNX2, and ALP was upregulated in isolated aortic SMCs from KL(-/-) mice, suggesting that KL deficiency causes osteoblastic transitions in vascular SMCs.
Conclusion: This study reveals a previously unidentified role of KL in regulating vascular function and arterial compliance. KL deficiency impairs vascular endothelial function, decreases elastin content, and causes vascular calcification leading to arterial stiffening. KL deficiency promotes osteoblastic transition in arterial SMCs.
- © 2013 by American Heart Association, Inc.