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

Jian Xie, Seungkuy Cha, Sung Wan An, Makoto Kuro-O, Lutz Birnbaumer, Chou Long Huang

Research output: Contribution to journalArticle

139 Citations (Scopus)

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.

Original languageEnglish
Article number1238
JournalNature Communications
Volume3
DOIs
Publication statusPublished - 2012 Dec 1

Fingerprint

mice
Down-Regulation
Cardiomegaly
Pathology
Phosphatidylinositols
Membrane Proteins
Phosphotransferases
Aging of materials
pathogenesis
deletion
1-Phosphatidylinositol 4-Kinase
Exocytosis
abnormalities
pathology
kidneys
Cardiomyopathies
Cardiac Myocytes
Heart Failure
membranes
proteins

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Xie, Jian ; Cha, Seungkuy ; An, Sung Wan ; Kuro-O, Makoto ; Birnbaumer, Lutz ; Huang, Chou Long. / Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. In: Nature Communications. 2012 ; Vol. 3.
@article{6e9bb7619acb4720bdc9bb0a4c0675ce,
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.",
author = "Jian Xie and Seungkuy Cha and An, {Sung Wan} and Makoto Kuro-O and Lutz Birnbaumer and Huang, {Chou Long}",
year = "2012",
month = "12",
day = "1",
doi = "10.1038/ncomms2240",
language = "English",
volume = "3",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. / Xie, Jian; Cha, Seungkuy; An, Sung Wan; Kuro-O, Makoto; Birnbaumer, Lutz; Huang, Chou Long.

In: Nature Communications, Vol. 3, 1238, 01.12.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart

AU - Xie, Jian

AU - Cha, Seungkuy

AU - An, Sung Wan

AU - Kuro-O, Makoto

AU - Birnbaumer, Lutz

AU - Huang, Chou Long

PY - 2012/12/1

Y1 - 2012/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84871726896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871726896&partnerID=8YFLogxK

U2 - 10.1038/ncomms2240

DO - 10.1038/ncomms2240

M3 - Article

C2 - 23212367

AN - SCOPUS:84871726896

VL - 3

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 1238

ER -