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TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling

Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the trans...

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Autores principales: Kitajima, Naoyuki, Numaga-Tomita, Takuro, Watanabe, Masahiko, Kuroda, Takuya, Nishimura, Akiyuki, Miyano, Kei, Yasuda, Satoshi, Kuwahara, Koichiro, Sato, Yoji, Ide, Tomomi, Birnbaumer, Lutz, Sumimoto, Hideki, Mori, Yasuo, Nishida, Motohiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105134/
https://www.ncbi.nlm.nih.gov/pubmed/27833156
http://dx.doi.org/10.1038/srep37001
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author Kitajima, Naoyuki
Numaga-Tomita, Takuro
Watanabe, Masahiko
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
author_facet Kitajima, Naoyuki
Numaga-Tomita, Takuro
Watanabe, Masahiko
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
author_sort Kitajima, Naoyuki
collection PubMed
description Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca(2+)-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca(2+)-dependent Nox2 activation through TRPC3-mediated background Ca(2+) entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca(2+) influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca(2+) influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities.
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spelling pubmed-51051342016-11-17 TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling Kitajima, Naoyuki Numaga-Tomita, Takuro Watanabe, Masahiko Kuroda, Takuya Nishimura, Akiyuki Miyano, Kei Yasuda, Satoshi Kuwahara, Koichiro Sato, Yoji Ide, Tomomi Birnbaumer, Lutz Sumimoto, Hideki Mori, Yasuo Nishida, Motohiro Sci Rep Article Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca(2+)-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca(2+)-dependent Nox2 activation through TRPC3-mediated background Ca(2+) entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca(2+) influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca(2+) influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities. Nature Publishing Group 2016-11-11 /pmc/articles/PMC5105134/ /pubmed/27833156 http://dx.doi.org/10.1038/srep37001 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Kitajima, Naoyuki
Numaga-Tomita, Takuro
Watanabe, Masahiko
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
title TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
title_full TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
title_fullStr TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
title_full_unstemmed TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
title_short TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
title_sort trpc3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105134/
https://www.ncbi.nlm.nih.gov/pubmed/27833156
http://dx.doi.org/10.1038/srep37001
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