Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart.
Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart.
复制标题
DOI：
10.1038/ncomms2240
复制
发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Klotho是一种主要在肾脏中产生的膜蛋白，具有一定的抗衰老作用。衰老会增加患心力衰竭的风险；Klotho是否具有心脏保护作用尚不清楚。在这里，我们发现kloho缺陷小鼠没有基线心脏异常，但在应激反应中发生夸张的病理性心脏肥大和重塑。Klotho对正常小鼠的心脏保护作用是通过下调心脏中TRPC6通道介导的。我们证明了Trpc6的缺失可以防止kloho缺陷小鼠应激诱导的过度心脏重塑。此外，心脏特异性TRPC6过表达的小鼠发生自发性心脏肥大和重构。Klotho过表达改善了这些小鼠的心脏病变，提高了它们的长期存活率。体循环中存在的可溶性Klotho通过阻断TRPC6通道的磷酸肌苷-3激酶依赖性胞外分泌来抑制心肌细胞中的TRPC6电流。这些结果为心肌病的发病机制提供了新的视角，为心肌病的治疗开辟了新的途径。
Klotho is a membrane protein predominantly produced in the kidney that exerts some anti-ageing effects. Ageing is associated with an increased risk of heart failure; whether Klotho is cardioprotective is unknown. Here we show that Klotho-deficient mice have no baseline cardiac abnormalities but develop exaggerated pathological cardiac hypertrophy and remodeling in response to stress. Cardioprotection by Klotho in normal mice is mediated by downregulation of TRPC6 channels in the heart. We demonstrate that deletion of Trpc6 prevents stress-induced exaggerated cardiac remodeling in Klotho-deficient mice. Furthermore, mice with heart-specific overexpression of TRPC6 develop spontaneous cardiac hypertrophy and remodeling. Klotho overexpression ameliorates cardiac pathologies in these mice and improves their long-term survival. Soluble Klotho present in the systemic circulation inhibits TRPC6 currents in cardiomyocytes by blocking phosphoinositide-3-kinase-dependent exocytosis of TRPC6 channels. These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease.
登录
查看更多内容
影响因子：
5
作者：
Koitabashi N;Aiba T;Hesketh GG;Rowell J;Zhang M;Takimoto E;Tomaselli GF;Kass DA
通讯作者：
Kass DA
影响因子：
5.3
作者：
Dietrich, A;Schnitzler, MMY;Birnbaumer, L
通讯作者：
Birnbaumer, L
影响因子：
9.2
作者：
An, Sung-Wan;Cha, Seung-Kuy;Huang, Chou-Long
通讯作者：
Huang, Chou-Long
影响因子：
11.5
作者：
Abramovitz, Lilach;Rubinek, Tamar;Wolf, Ido
通讯作者：
Wolf, Ido
影响因子：
4.8
作者：
Bush, Erik W.;Hood, David B.;McKinsey, Timothy A.
通讯作者：
McKinsey, Timothy A.