Klotho Deficiency Causes Heart Aging via Impairing the Nrf2-GR Pathway.
Klotho Deficiency Causes Heart Aging via Impairing the Nrf2-GR Pathway.
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DOI：
10.1161/circresaha.120.317348
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发表时间：
2021-02-19
影响因子：
20.1
通讯作者：
Sun Z
中科院分区：
文献类型：
--
作者：
Chen K;Wang S;Sun QW;Zhang B;Ullah M;Sun Z
心脏衰老是导致心力衰竭的一个重要因素，影响着大量人群，但人们对此仍知之甚少。本研究的目的是调查 Klotho 是否在心脏衰老中发挥作用。老年小鼠（24 个月）的心功能下降，表现为缩短分数、射血分数和心输出量的下降。老年小鼠的心脏大小和重量、心肌细胞大小和心脏纤维化均增加，表明衰老导致心脏肥大和重塑。年老小鼠的循环 Klotho 水平显着下降，这促使我们研究 Klotho 下降是否可能导致心脏衰老。我们发现 Klotho 基因突变 (KL−/−) 很大程度上降低了血清 Klotho 水平并损害了心脏功能。有趣的是，补充外源性分泌型 Klotho 可以预防老年小鼠和 KL (−/−) 小鼠的心力衰竭、肥大和重构。分泌型 Klotho 治疗可抑制老年小鼠和 KL (−/−) 小鼠的过度心脏氧化应激、衰老和细胞凋亡。 KL (−/−) 小鼠的血清磷酸盐水平保持在正常范围内，表明 Klotho 缺乏引起的心脏衰老与磷酸盐代谢无关。从机制上讲，Klotho 缺陷通过抑制转录因子 Nrf2 来抑制心脏中谷胱甘肽还原酶 (GR) 的表达和活性。此外，心脏特异性的 GR 过度表达可以防止老年小鼠和 KL (−/−) 小鼠的过度氧化应激、细胞凋亡和心力衰竭。 Klotho 缺陷通过损害 Nrf2-GR 通路导致心脏衰老。补充外源性分泌型 Klotho 是治疗衰老相关心肌病和心力衰竭的一种有前途的治疗策略。
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 Klotho 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 glutathione reductase (GR) expression and activity in the heart via inhibition of transcription factor Nrf2. 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.