Curcumin, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Acetyltransferase, Attenuate Cardiac Hypertrophy

Introduction: Recent studies have suggested that p300 plays a critical role in cardiac hypertrophy. Pharmacological modulators of p300-histone acetyltransferases (HAT) activity may prevent cardiac hypertrophy and failure. Curcumin is a natural inhibitor of the HAT p300/CREB-binding protein (CBP) and can inhibit histone acetylation. Hypothesis: Curcumin can inhibit cardiac hypertrophy through blockade of p300-HAT activity. Methods and Results: C57BL/6J mice mice were randomized to Aortic banding (AB) or sham operation; and further randomized to curcumin or saline control. An earlier dose finding study established that 75 mg/kg/day of curcumin is efficacious yet devoid of toxicity. The animals were sacrificed at 8 weeks after surgery to assess cardiac hypertrophy. In the AB groups, curcumin significantly attenuated heart weight/body weight (HW/BW) and lung weight/body weight (LW/BW) ratios, and reduced LV end-diastolic and end-systolic diameters when compared to saline controls. Furthermore, the amount of inflammatory and fibrosis induced by AB were significantly attenuated by curcumin. Similarly, mRNA expressions of ANP and BNP induced by AB were reduced with curcumin. Importantly, activated NF-κB signaling through nuclear translocation, and TGF-β1 signaling through smad 2/3/4 translocations were blocked by curcumin. Further evidence demonstrated that curcumin can reverse established cardiac hypertrophy as estimated by amelioration of HW/BW, LW/BW, echocardiographic measurements as well as cardiac ANP and BNP mRNA levels. Our further data showed that the acetylation of histones H3 and H4 in response to hypertrophy stimuli was inhibited by curcumin. Furthermore, exposure to curcumin blocked PE-induced increase in p300-HAT activity as well as acetylation and DNA binding activity of GATA4. This was confirmed further by demonstrating that infection of Adp300-HAT mutant inhibits PE-induced cardiac hypertrophy by blocking p300-HAT activity, and acetylation and DNA binding activity of GATA4. Conversely, infection with Adp300 augments hypertrophy by increasing p300-HAT activity. In conclusion: We conclude that curcumin can prevent the development of cardiac hypertrophy and can also reverse established cardiac hypertrophy by blocking p300-HAT-dependent hypertrophy, inflammation and fibrosis. Translation of this finding to the clinic may have important therapeutic potential.