Cargando…
Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling
Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca(2+) is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we inv...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691336/ https://www.ncbi.nlm.nih.gov/pubmed/33244105 http://dx.doi.org/10.1038/s42003-020-01443-w |
_version_ | 1783614267421884416 |
---|---|
author | Kohno, Michiaki Kobayashi, Shigeki Yamamoto, Takeshi Yoshitomi, Ryosuke Kajii, Toshiro Fujii, Shohei Nakamura, Yoshihide Kato, Takayoshi Uchinoumi, Hitoshi Oda, Tetsuro Okuda, Shinichi Watanabe, Kenji Mizukami, Yoichi Yano, Masafumi |
author_facet | Kohno, Michiaki Kobayashi, Shigeki Yamamoto, Takeshi Yoshitomi, Ryosuke Kajii, Toshiro Fujii, Shohei Nakamura, Yoshihide Kato, Takayoshi Uchinoumi, Hitoshi Oda, Tetsuro Okuda, Shinichi Watanabe, Kenji Mizukami, Yoichi Yano, Masafumi |
author_sort | Kohno, Michiaki |
collection | PubMed |
description | Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca(2+) is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigate whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca(2+) leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. In the very initial phase of pressure-overload induced cardiac hypertrophy, when cardiac contractile function is preserved, reactive oxygen species (ROS)-mediated RyR2 destabilization already occurs in association with relaxation dysfunction. Further, stabilizing RyR2 by enhancing the binding affinity of CaM to RyR2 completely inhibits hypertrophic signaling and improves survival. Our study uncovers a critical missing link between RyR2 destabilization and cardiac hypertrophy. |
format | Online Article Text |
id | pubmed-7691336 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76913362020-11-30 Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling Kohno, Michiaki Kobayashi, Shigeki Yamamoto, Takeshi Yoshitomi, Ryosuke Kajii, Toshiro Fujii, Shohei Nakamura, Yoshihide Kato, Takayoshi Uchinoumi, Hitoshi Oda, Tetsuro Okuda, Shinichi Watanabe, Kenji Mizukami, Yoichi Yano, Masafumi Commun Biol Article Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca(2+) is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigate whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca(2+) leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. In the very initial phase of pressure-overload induced cardiac hypertrophy, when cardiac contractile function is preserved, reactive oxygen species (ROS)-mediated RyR2 destabilization already occurs in association with relaxation dysfunction. Further, stabilizing RyR2 by enhancing the binding affinity of CaM to RyR2 completely inhibits hypertrophic signaling and improves survival. Our study uncovers a critical missing link between RyR2 destabilization and cardiac hypertrophy. Nature Publishing Group UK 2020-11-26 /pmc/articles/PMC7691336/ /pubmed/33244105 http://dx.doi.org/10.1038/s42003-020-01443-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kohno, Michiaki Kobayashi, Shigeki Yamamoto, Takeshi Yoshitomi, Ryosuke Kajii, Toshiro Fujii, Shohei Nakamura, Yoshihide Kato, Takayoshi Uchinoumi, Hitoshi Oda, Tetsuro Okuda, Shinichi Watanabe, Kenji Mizukami, Yoichi Yano, Masafumi Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
title | Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
title_full | Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
title_fullStr | Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
title_full_unstemmed | Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
title_short | Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
title_sort | enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691336/ https://www.ncbi.nlm.nih.gov/pubmed/33244105 http://dx.doi.org/10.1038/s42003-020-01443-w |
work_keys_str_mv | AT kohnomichiaki enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT kobayashishigeki enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT yamamototakeshi enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT yoshitomiryosuke enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT kajiitoshiro enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT fujiishohei enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT nakamurayoshihide enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT katotakayoshi enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT uchinoumihitoshi enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT odatetsuro enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT okudashinichi enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT watanabekenji enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT mizukamiyoichi enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling AT yanomasafumi enhancingcalmodulinbindingtocardiacryanodinereceptorcompletelyinhibitspressureoverloadinducedhypertrophicsignaling |