Curcumin prevents and reverses murine cardiac hypertrophy (Retracted article. See vol 119, pg 2113, 2009)
Curcumin prevents and reverses murine cardiac hypertrophy (Retracted article. See vol 119, pg 2113, 2009)
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DOI：
10.1172/jci32865
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发表时间：
2008-03-01
影响因子：
15.9
通讯作者：
Liu, Peter P.
中科院分区：
文献类型：
--
作者：
Li, Hong-Liang;Liu, Chen;Liu, Peter P.
染色质重塑，尤其是组蛋白乙酰化，在病理性心肌肥厚和心力衰竭的进展中起着关键作用。姜黄素是一种天然多酚化合物，在香料姜黄中含量丰富，是已知的组蛋白乙酰化抑制因子，我们推测姜黄素通过破坏p300组蛋白乙酰转移酶依赖(p300-HAT依赖)的转录激活来抑制心肌肥厚。我们使用原代培养的大鼠心肌细胞和成纤维细胞以及两种公认的心肌肥大小鼠模型来验证这一假说。姜黄素抑制苯肾上腺素(PE)诱导的体外心肌肥厚，呈剂量依赖关系。此外，姜黄素可以预防和逆转主动脉缩窄(AB)和PE注射所致的小鼠心肌肥厚，通过心脏重量/体重和肺重量/体重比率、超声心动图参数和肥厚标志物的基因表达来评估。进一步的研究表明，姜黄素通过阻断p300-HAT活性来抑制组蛋白乙酰化、GATA4乙酰化和DNA结合活性。姜黄素还通过阻断依赖p300-HAT的信号通路来阻断AB诱导的炎症和纤维化。我们的结果表明，姜黄素有可能通过抑制p300-HAT活性和下游的GATA4、NF-kappa B和TGF-β-Smad信号通路来保护心肌肥大、炎症和纤维化。
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 wen 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-kappa B, and TGF-beta-Smad signaling pathways.