Application of Curcumin to Heart Failure Therapy by Targeting Transcriptional Pathway in Cardiomyocytes

Abstract

Heart failure is one of the leading causes of death throughout the world. During the development and deterioration processes of heart failure, cardiomyocytes undergo maladaptive hypertrophy by altering hypertrophy-related gene expression. The zinc finger protein GATA4 is one of the transcription factors involved in the regulation of cardiomyocyte hypertrophy. In response to hypertrophic stimuli such as the synaptic nervous and rennin-angiotensin systems, GATA4 forms a large complex with various functional proteins including an intrinsic histone acetyltransferase, p300, and the disruption of this complex results in the inhibition of hypertrophic responses in cardiomyocytes. While such a transcriptional signal pathway is recognized as a critical event during cardiomyocyte hypertrophy, pharmacological heart failure therapy that targets this pathway has not been established. In order to develop novel heart failure therapy targeting the pathway in cardiomyocytes, we have studied the potential of curcumin, a p300 histone acetyltransferase inhibitor, as an agent for novel heart failure therapy. In this review, we describe a recent study on the cardiac transcriptional signal pathway, especially p300/GATA4 pathway, and a novel heart failure therapy using curcumin.

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

“…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. 5,56,57) During the past two decades, many therapeutic agents have been developed for the treatment of patients with systolic heart failure. Long-term treatment with angiotensin-converting enzyme I, angiotensin II type 1 receptor blockers, mineralocorticoid receptor antagonists, and β-adrenergic receptor antagonists (beta blockers) improves symptoms, hemodynamics, and clinical outcomes.…”

“…Transcription factors such as myocyte enhancer factor 2 (MEF2), 3) serum response factor (SRF), 4) GATA binding protein 4 (GATA4), 5) AP-1, 6) neuron-restrictive silencer factor (NRSF), 7) nuclear factor of activated T cells (NFAT), 8) and myocardin 9) have been implicated as mediators of the fetal gene program that are associated with cardiac hypertrophy and heart failure. Among these, we have investigated the function of GATA4 and p300, a histone acetyltransferase (HAT) and a GATA4 coactivator, in the progression of cardiac hypertrophy and heart failure.…”

The effects of curcumin‐containing supplements on biomarkers of inflammation and oxidative stress: A systematic review and meta‐analysis of randomized controlled trials

“…Previous studies have introduced potential anti‐inflammatory and antioxidant effects for curcumin, which may justify its therapeutic properties in different chronic conditions including cancer and myocardial events (Katanasaka, Sunagawa, Hasegawa, & Morimoto, ; Wang, Wang, Tootle, Philip, & Zhao, ). In a meta‐analysis conducted on six trials comprising 342 subjects, supplementation with curcuminoids significantly reduced C‐reactive protein (CRP) concentrations (Sahebkar, ).…”

Optimal Dose-Setting Study of Curcumin for Improvement of Left Ventricular Systolic Function After Myocardial Infarction in Rats

“…Namely, p300 is necessary for both myocardial cell growth and survival. These p300 roles in the heart are mainly dependent on its HAT activity since p300 plays roles in the transcriptional regulation of cardiac hypertrophy and apoptosis (41). Thus, the control of not only protein levels of cardiomyocyte p300 but also its HAT activity may be important for maintaining the homeostasis of cardiomyocytes.…”