title: Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart.
abstract: 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.
authors.affiliation: Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xie
authors.forename: Seung-Kuy
authors.initials: SK
authors.lastname: Cha
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: An
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology; D009202:Cardiomyopathies / Q000503:physiopathology*; D015536:Down-Regulation; D005966:Glucuronidase / Q000502:physiology*; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D050052:TRPC Cation Channels / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins