Tyrosine phosphorylation of RACK1 triggers cardiomyocyte hypertrophy by regulating the interaction between p300 and GATA4

Abstract

The zinc finger protein GATA4 is a transcription factor involved in cardiomyocyte hypertrophy. It forms a functional complex with the intrinsic histone acetyltransferase (HAT) p300. The HAT activity of p300 is required for the acetylation and transcriptional activity of GATA4, as well as for cardiomyocyte hypertrophy and the development of heart failure. In the present study, we have identified Receptor for Activated Protein Kinase C1 (RACK1) as a novel GATA4-binding protein using tandem affinity purification and mass spectrometry analyses. We found that exogenous RACK1 repressed phenylephrine (PE)-induced hypertrophic responses, such as myofibrillar organization, increased cell size, and hypertrophy-associated gene transcription, in cultured cardiomyocytes. RACK1 physically interacted with GATA4 and the overexpression of RACK1 reduced PE-induced formation of the p300/GATA4 complex and the acetylation and DNA binding activity of GATA4. In response to hypertrophic stimulation in cultured cardiomyocytes and in the hearts of hypertensive heart disease model rats, the tyrosine phosphorylation of RACK1 was increased, and the binding between GATA4 and RACK1 was reduced. In addition, the tyrosine phosphorylation of RACK1 was required for the disruption of the RACK1/GATA4 complex and for the formation of the p300/GATA4 complex. These findings demonstrate that RACK1 is involved in p300/GATA4-dependent hypertrophic responses in cardiomyocytes and is a promising therapeutic target for heart failure.

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

“…Immunofluorescent staining and measurement of cardiomyocyte surface area. Immunofluorescent staining of the cultured cardiomyocytes was performed as described previously 12,29 .…”

Regulation of Cardiac Transcription Factor GATA4 by Post-Translational Modification in Cardiomyocyte Hypertrophy and Heart Failure

“…In hypertrophied cardiomyocytes and failing hearts, RACK1 is phosphorylated and dissociated from GATA4, leading to the activation of the p300/GATA4 pathway. 55) Conclusion: To establish a fundamental pharmacologic therapy for heart failure, we examined the transcriptional pathway in cardiomyocytes and identified the p300/GATA4 pathway. Moreover, we demonstrated that curcumin, a p300-specific HAT inhibitor, prevents cardiomyocyte hypertrophy and improves the development of heart failure in animal models; a clinical study of heart failure patients with hypertension and cardiac hypertrophy is currently underway.…”

Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

“…When GATA4 is phosphorylated, its binding activity to DNA is activated, which up-regulates the gene transcription involved in pathological cardiac hypertrophy [6,7]. In response to hypertrophic stimuli, GATA4 forms a large complex with ERK, NFAT3, CDK9, RACK1, MEF2, and p300 [6,[8][9][10][11][12]. GATA4 plays a central role in this hypertrophic response complex, suggesting that it may be a specific target for the prevention of HF development [6,12].…”