Curcumin prevents and reverses murine cardiac hypertrophy.
Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase-dependent (p300-HAT-dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PE-induced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT-dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-kappaB, and TGF-beta-Smad signaling pathways.
Li
Hong-Liang
HL
Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Liu
Chen
C
de Couto
Geoffrey
G
Ouzounian
Maral
M
Sun
Mei
M
Wang
Ai-Bing
AB
Huang
Yue
Y
He
Cheng-Wei
CW
Shi
Yu
Y
Chen
Xin
X
Nghiem
Mai P
MP
Liu
Youan
Y
Chen
Manyin
M
Dawood
Fayez
F
Fukuoka
Masahiro
M
Maekawa
Yuichiro
Y
Zhang
Liyong
L
Leask
Andrew
A
Ghosh
Asish K
AK
Kirshenbaum
Lorrie A
LA
Liu
Peter P
PP
D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control*; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005355:Fibrosis; D050991:GATA4 Transcription Factor / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors; D000099224:p300-CBP-Associated Factor
D003474:Curcumin; D004247:DNA; D004791:Enzyme Inhibitors; D050991:GATA4 Transcription Factor; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C484171:Gata4 protein, mouse