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

Area of Science:

• Cardiovascular Biology
• Molecular Pharmacology
• Epigenetics

Background:

• The p300 histone acetyltransferase (HAT) is crucial in heart failure development.
• Curcumin (CUR) inhibits p300 HAT and shows promise in heart failure models.
• Limited structure-activity relationship studies exist for CUR analogs in cardiomyocyte hypertrophy.

Purpose of the Study:

• To investigate the efficacy of prenylated pyrazolo curcumin (PPC) and curcumin pyrazole (PyrC) in suppressing cardiomyocyte hypertrophy.
• To elucidate the molecular mechanisms underlying the actions of PyrC on p300 HAT and Cdk9 kinase activity.

Main Methods:

• Cultured cardiomyocytes were treated with CUR, PPC, or PyrC and stimulated with phenylephrine (PE).
• Western blotting and in vitro HAT assays were used to assess histone acetylation and p300 HAT activity.
• Cdk9 kinase activity, p300 phosphorylation, and Cdk9-CyclinT1 binding were examined using immunoprecipitation-Western blotting.

Main Results:

• PyrC, at lower concentrations than CUR, inhibited PE-induced cardiomyocyte hypertrophy and histone acetylation.
• PyrC did not directly inhibit p300 HAT activity in vitro.
• PyrC suppressed Cdk9-mediated phosphorylation of p300 and inhibited Cdk9 binding to CyclinT1.

Conclusions:

• PyrC prevents cardiomyocyte hypertrophy by indirectly suppressing p300 HAT activity.
• PyrC inhibits Cdk9 kinase activity, impacting both p300 HAT and RNA polymerase II transcription.
• PyrC represents a promising therapeutic agent for cardiomyocyte hypertrophy and heart failure.