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Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex
The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure m...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9227296/ https://www.ncbi.nlm.nih.gov/pubmed/35745840 http://dx.doi.org/10.3390/pharmaceutics14061269 |
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author | Funamoto, Masafumi Sunagawa, Yoichi Gempei, Mai Shimizu, Kana Katanasaka, Yasufumi Shimizu, Satoshi Hamabe-Horiike, Toshihide Appendino, Giovanni Minassi, Alberto Koeberle, Andreas Komiyama, Maki Mori, Kiyoshi Hasegawa, Koji Morimoto, Tatsuya |
author_facet | Funamoto, Masafumi Sunagawa, Yoichi Gempei, Mai Shimizu, Kana Katanasaka, Yasufumi Shimizu, Satoshi Hamabe-Horiike, Toshihide Appendino, Giovanni Minassi, Alberto Koeberle, Andreas Komiyama, Maki Mori, Kiyoshi Hasegawa, Koji Morimoto, Tatsuya |
author_sort | Funamoto, Masafumi |
collection | PubMed |
description | The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure models. However, few structure–activity relationship studies on cardiomyocyte hypertrophy using CUR have been conducted. To evaluate if prenylated pyrazolo curcumin (PPC) and curcumin pyrazole (PyrC) can suppress cardiomyocyte hypertrophy, cultured cardiomyocytes were treated with CUR, PPC, or PyrC and then stimulated with phenylephrine (PE). PE-induced cardiomyocyte hypertrophy was inhibited by PyrC but not PPC at a lower concentration than CUR. Western blotting showed that PyrC suppressed PE-induced histone acetylation. However, an in vitro HAT assay showed that PyrC did not directly inhibit p300-HAT activity. As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity, the effects of CUR and PyrC on the kinase activity of Cdk9 were examined. Phosphorylation of p300 by Cdk9 was suppressed by PyrC. Immunoprecipitation-WB showed that PyrC inhibits Cdk9 binding to CyclinT1 in cultured cardiomyocytes. PyrC may prevent cardiomyocyte hypertrophic responses by indirectly suppressing both p300-HAT activity and RNA polymerase II transcription elongation activity via inhibition of Cdk9 kinase activity. |
format | Online Article Text |
id | pubmed-9227296 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92272962022-06-25 Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex Funamoto, Masafumi Sunagawa, Yoichi Gempei, Mai Shimizu, Kana Katanasaka, Yasufumi Shimizu, Satoshi Hamabe-Horiike, Toshihide Appendino, Giovanni Minassi, Alberto Koeberle, Andreas Komiyama, Maki Mori, Kiyoshi Hasegawa, Koji Morimoto, Tatsuya Pharmaceutics Article The intrinsic histone acetyltransferase (HAT), p300, has an important role in the development and progression of heart failure. Curcumin (CUR), a natural p300-specific HAT inhibitor, suppresses hypertrophic responses and prevents deterioration of left-ventricular systolic function in heart-failure models. However, few structure–activity relationship studies on cardiomyocyte hypertrophy using CUR have been conducted. To evaluate if prenylated pyrazolo curcumin (PPC) and curcumin pyrazole (PyrC) can suppress cardiomyocyte hypertrophy, cultured cardiomyocytes were treated with CUR, PPC, or PyrC and then stimulated with phenylephrine (PE). PE-induced cardiomyocyte hypertrophy was inhibited by PyrC but not PPC at a lower concentration than CUR. Western blotting showed that PyrC suppressed PE-induced histone acetylation. However, an in vitro HAT assay showed that PyrC did not directly inhibit p300-HAT activity. As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity, the effects of CUR and PyrC on the kinase activity of Cdk9 were examined. Phosphorylation of p300 by Cdk9 was suppressed by PyrC. Immunoprecipitation-WB showed that PyrC inhibits Cdk9 binding to CyclinT1 in cultured cardiomyocytes. PyrC may prevent cardiomyocyte hypertrophic responses by indirectly suppressing both p300-HAT activity and RNA polymerase II transcription elongation activity via inhibition of Cdk9 kinase activity. MDPI 2022-06-15 /pmc/articles/PMC9227296/ /pubmed/35745840 http://dx.doi.org/10.3390/pharmaceutics14061269 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Funamoto, Masafumi Sunagawa, Yoichi Gempei, Mai Shimizu, Kana Katanasaka, Yasufumi Shimizu, Satoshi Hamabe-Horiike, Toshihide Appendino, Giovanni Minassi, Alberto Koeberle, Andreas Komiyama, Maki Mori, Kiyoshi Hasegawa, Koji Morimoto, Tatsuya Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex |
title | Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex |
title_full | Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex |
title_fullStr | Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex |
title_full_unstemmed | Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex |
title_short | Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex |
title_sort | pyrazole-curcumin suppresses cardiomyocyte hypertrophy by disrupting the cdk9/cyclint1 complex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9227296/ https://www.ncbi.nlm.nih.gov/pubmed/35745840 http://dx.doi.org/10.3390/pharmaceutics14061269 |
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