Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis (K.C., S.W., Q.W.S., B.Z., Z.S.).
Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City (K.C., S.W., M.U., Z.S.).
Circ Res. 2021 Feb 19;128(4):492-507. doi: 10.1161/CIRCRESAHA.120.317348. Epub 2020 Dec 18.
Cardiac aging is an important contributing factor for heart failure, which affects a large population but remains poorly understood.
The purpose of this study is to investigate whether Klotho plays a role in cardiac aging.
Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size, and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that gene mutation (KL-/-) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (-/-) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (-/-) mice. Serum phosphate levels in KL (-/-) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed GR (glutathione reductase) expression and activity in the heart via inhibition of transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2). Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (-/-) mice.
Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.
心脏衰老（cardiac aging）是心力衰竭（heart failure）的一个重要致病因素，心力衰竭影响着庞大的人群，但目前人们对其了解甚少。
本研究旨在探究 Klotho 是否在心脏衰老中发挥作用。
衰老（old）小鼠（24 月龄）的心功能下降，表现为短轴缩短率（fractional shortening）、射血分数（ejection fraction）和心输出量（cardiac output）降低。衰老小鼠的心脏增大、重量增加，心肌细胞增大，心脏纤维化（cardiac fibrosis）增加，表明衰老导致心脏肥大和重塑（remodeling）。衰老小鼠的循环 Klotho 水平显著降低，促使我们研究 Klotho 降低是否会导致心脏衰老。我们发现，基因敲除（gene knockout，KL-/-）小鼠的 Klotho 基因缺失（mutation）大大降低了血清 Klotho 水平并损害了心功能。有趣的是，外源性分泌型 Klotho 的补充（supplementation）预防了衰老和 KL-/-小鼠的心衰、心脏肥大和重塑。分泌型 Klotho 处理抑制了衰老和 KL-/-小鼠的心脏过度氧化应激（oxidative stress）、衰老和细胞凋亡（apoptosis）。KL-/-小鼠的血清磷酸盐水平（phosphate levels）保持在正常范围内，提示 Klotho 缺乏诱导的心脏衰老与磷酸盐代谢无关。机制上，Klotho 缺乏通过抑制转录因子 Nrf2（nuclear factor-erythroid 2 p45-related factor 2）抑制心脏中的 GR（glutathione reductase）表达和活性。此外，心脏特异性过表达 GR 可预防衰老和 KL-/-小鼠的心脏过度氧化应激、细胞凋亡和心力衰竭。
Klotho 缺乏通过损害 Nrf2-GR 通路导致心脏衰老。外源性分泌型 Klotho 的补充为衰老相关心肌病和心力衰竭提供了一种有前景的治疗策略。
