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

Abstract

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.

Roles of histone acetylation sites in cardiac hypertrophy and heart failure

“…Acetylation of H3K9 and H3K27 has also been suggested to be involved in the expression of GATA4, as GATA4 is involved in the development of HF and the fetal gene is reactivated during HF, suggesting that the acetylation of H3K4 may be involved in cardiac hypertrophy and HF ( 25 , 26 ). Many reports have suggested that the acetylation of H3K9 by p300 causes cardiomyocyte hypertrophy ( 3 , 4 , 27 – 30 ). Furthermore, H3K9 acetylation is increased during cardiac hypertrophy and HF in TAC and Dahl rats ( 4 , 26 , 31 ).…”

“…Acetylation of histones by p300 is involved in cardiac hypertrophy and heart failure ( 46 , 47 ). Hypertrophic stress increases HAT activity and histone acetylation, as p300 is regulated by several proteins, including ERK1/2, Akt, and Cdk9 ( 3 ). However, for HATs such as GCN5, CBP, and PCAF, the relationship with histone acetylation is unclear, although an association between cardiac hypertrophy and heart failure has been reported ( 48 – 50 ).Curcumin, a natural product, inhibits histone acetylation by blocking the HAT activity of p300, thereby improving cardiomyocyte hypertrophy and HF ( 32 ).…”

“…Curcumin has also been reported to inhibit heart failure with preserved ejection fraction in Dahl rats ( 47 ). Recently, curcumin-based derivatives and analogs have been shown to have beneficial effects in HF ( 3 , 4 ). Anacardic and eicosapentaenoic acids improve HF by inhibiting the HAT activity of p300.…”

“…Various CVDs can lead to HF via pathological cardiac hypertrophy. Cardiac hypertrophy is an important process of cardiac remodeling that is often caused by preload, such as hypertension, or afterload, such as myocardial infarction ( 2 , 3 ). Cardiac hypertrophy is a compensatory mechanism that reduces oxygen consumption, normalizes the ventricular systolic pressure, and improves the ejection function.…”