Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart

Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart

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 deve...

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Main Authors: Xie, Jian, Cha, Seung-Kuy, An, Sung-Wan, Kuro-o, Makoto, Birnbaumer, Lutz, Huang, Chou-Long
Format: Online
Language:English
Published: 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526952/
id pubmed-3526952
recordtype oai_dc
spelling pubmed-35269522013-06-04 Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart Xie, Jian Cha, Seung-Kuy An, Sung-Wan Kuro-o, Makoto Birnbaumer, Lutz Huang, Chou-Long Article 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. 2012 /pmc/articles/PMC3526952/ /pubmed/23212367 http://dx.doi.org/10.1038/ncomms2240 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Xie, Jian
Cha, Seung-Kuy
An, Sung-Wan
Kuro-o, Makoto
Birnbaumer, Lutz
Huang, Chou-Long
spellingShingle Xie, Jian
Cha, Seung-Kuy
An, Sung-Wan
Kuro-o, Makoto
Birnbaumer, Lutz
Huang, Chou-Long
Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
author_facet Xie, Jian
Cha, Seung-Kuy
An, Sung-Wan
Kuro-o, Makoto
Birnbaumer, Lutz
Huang, Chou-Long
author_sort Xie, Jian
title Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
title_short Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
title_full Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
title_fullStr Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
title_full_unstemmed Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
title_sort cardioprotection by klotho through downregulation of trpc6 channels in the mouse heart
description 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.
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526952/
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