Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Nat Commun. 2012;3:1238. doi: 10.1038/ncomms2240.
Klotho is a membrane protein predominantly produced in the kidney that exerts some antiageing 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 remodelling 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 remodelling in Klotho-deficient mice. Furthermore, mice with heart-specific overexpression of TRPC6 develop spontaneous cardiac hypertrophy and remodelling. 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.
Klotho 是一种主要在肾脏中产生的膜蛋白，具有一些抗衰老作用。衰老与心力衰竭风险增加有关；Klotho 是否具有心脏保护作用尚不清楚。在这里，我们表明 Klotho 缺陷小鼠没有基线心脏异常，但在应激下会发生明显的病理性心肌肥厚和重塑。正常小鼠中 Klotho 的心脏保护作用是通过心脏中 TRPC6 通道的下调介导的。我们证明，TRPC6 的缺失可防止 Klotho 缺陷小鼠应激引起的心肌重塑过度。此外，心脏特异性过表达 TRPC6 的小鼠会自发发生心肌肥厚和重塑。Klotho 的过表达可改善这些小鼠的心脏病理学并提高其长期存活率。循环系统中存在的可溶性 Klotho 通过阻断磷酸肌醇-3-激酶依赖性 TRPC6 通道胞吐作用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，并为该疾病的治疗开辟了新的途径。
