Pyrazole-Curcumin Suppresses Cardiomyocyte Hypertrophy by Disrupting the CDK9/CyclinT1 Complex

Pharmaceutics

Alberto Minassi¹  Giovanni Appendino¹  Masafumi Funamoto²  Satoshi Shimizu²  Yoichi Sunagawa²  Toshihide Hamabe-Horiike²  Tatsuya Morimoto²  Mai Gempei²  Koji Hasegawa²  Kana Shimizu²  Yasufumi Katanasaka²  Maki Komiyama³  Andreas Koeberle⁴  Kiyoshi Mori⁵ 

[1] Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy;Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan;Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa Mukaihatacho, Fushimi-ku, Kyoto 612-8555, Japan;Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria;Shizuoka General Hospital, 4-27-27-1 Kitaando, Aoi-ku, Shizuoka 420-8527, Japan;

关键词: cardiomyocyte hypertrophy;    p300;    curcumin;    histone acetyltransferase;    Cdk9;    phosphorylation;   

DOI  :  10.3390/pharmaceutics14061269

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown