Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats
Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats
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DOI：
10.1111/j.1476-5381.2010.00637.x
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发表时间：
2010-04-01
影响因子：
7.3
通讯作者：
Brown, Lindsay
中科院分区：
文献类型：
--
作者：
Iyer, Abishek;Fenning, Andrew;Brown, Lindsay
背景与目的：组蛋白脱乙酰酶（HDAC）通过使组蛋白和其他蛋白质中的赖氨酸残基脱乙酰来沉默基因。 HDAC 抑制剂代表了一类具有抗炎活性的新型化合物。本研究调查了广谱 HDAC 抑制剂辛二酰苯胺异羟肟酸 (SAHA) 的治疗是否会预防心脏纤维化，这是醋酸去氧皮质酮 (DOCA) 盐大鼠心血管重塑的一部分。实验方法：对照和 DOCA 盐大鼠接受 SAHA（25 mg 中心点 kg-1 中心点·天 -1 s.c.）治疗 32 天。通过体内血压和兰根多夫灌注心脏、心室乳头肌和体外主动脉环的血压来评估心血管结构和功能的变化。通过组织学评估左心室胶原沉积。 主要结果：对 DOCA 盐大鼠施用 SAHA 减弱了以下参数：血浆中 20 多种促炎细胞因子浓度增加，炎症细胞浸润和间质胶原沉积增加，灌注心脏被动舒张僵硬度增加，乳头肌复极时动作电位持续时间延长 20% 和 90%，左心室肥厚发展，结论和意义：HDAC 抑制剂 SAHA 减弱了 DOCA 盐高血压大鼠的心血管重塑，并改善了心血管结构和功能，尤其是心脏和血管的纤维化，这可能是通过抑制炎症来实现的。控制心脏组蛋白或非组蛋白乙酰化是预防心脏重塑，特别是心脏纤维化的潜在治疗方法。
Background and purpose:Histone deacetylases (HDACs) silence genes by deacetylating lysine residues in histones and other proteins. HDAC inhibitors represent a new class of compounds with anti-inflammatory activity. This study investigated whether treatment with a broad spectrum HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), would prevent cardiac fibrosis, part of the cardiovascular remodelling in deoxycorticosterone acetate (DOCA)-salt rats.Experimental approach:Control and DOCA-salt rats were treated with SAHA (25 mg center dot kg-1 center dot day-1 s.c.) for 32 days. Changes in cardiovascular structure and function were assessed by blood pressure in vivo and in Langendorff perfused hearts, ventricular papillary muscle and in aortic rings in vitro. Left ventricular collagen deposition was assessed by histology.Key results:Administration of SAHA to DOCA-salt rats attenuated the following parameters: the increased concentration of over 20 pro-inflammatory cytokines in plasma, increased inflammatory cell infiltration and interstitial collagen deposition, increased passive diastolic stiffness in perfused hearts, prolongation of action potential duration at 20% and 90% of repolarization in papillary muscle, development of left ventricular hypertrophy, systolic hypertension and changes in vascular dysfunction.Conclusions and implications:The HDAC inhibitor, SAHA, attenuated the cardiovascular remodelling associated with DOCA-salt hypertensive rats and improved cardiovascular structure and function, especially fibrosis, in the heart and blood vessels, possibly by suppressing inflammation. Control of cardiac histone or non-histone protein acetylation is a potential therapeutic approach to preventing cardiac remodelling, especially cardiac fibrosis.