Institute of Molecular Cardiology, Division of Cardiovascular Medicine, University of Louisville, 580 S. Preston Street, Louisville, KY, 40292, USA.
Department of Medicine, Cardiovascular Innovation Institute, University of Louisville, Louisville, KY, USA.
Basic Res Cardiol. 2018 Nov 16;114(1):3. doi: 10.1007/s00395-018-0710-1.
Preclinical investigations support the concept that donor cells more oriented towards a cardiovascular phenotype favor repair. In light of this philosophy, we previously identified HDAC1 as a mediator of cardiac mesenchymal cell (CMC) cardiomyogenic lineage commitment and paracrine signaling potency in vitro-suggesting HDAC1 as a potential therapeutically exploitable target to enhance CMC cardiac reparative capacity. In the current study, we examined the effects of pharmacologic HDAC1 inhibition, using the benzamide class 1 isoform-selective HDAC inhibitor entinostat (MS-275), on CMC cardiomyogenic lineage commitment and CMC-mediated myocardial repair in vivo. Human CMCs pre-treated with entinostat or DMSO diluent control were delivered intramyocardially in an athymic nude rat model of chronic ischemic cardiomyopathy 30 days after a reperfused myocardial infarction. Indices of cardiac function were assessed by echocardiography and left ventricular (LV) Millar conductance catheterization 35 days after treatment. Compared with naïve CMCs, entinostat-treated CMCs exhibited heightened capacity for myocyte-like differentiation in vitro and superior ability to attenuate LV remodeling and systolic dysfunction in vivo. The improvement in CMC therapeutic efficacy observed with entinostat pre-treatment was not associated with enhanced donor cell engraftment, cardiomyogenesis, or vasculogenesis, but instead with more efficient inhibition of myocardial fibrosis and greater increase in myocyte size. These results suggest that HDAC inhibition enhances the reparative capacity of CMCs, likely via a paracrine mechanism that improves ventricular compliance and contraction and augments myocyte growth and function.
临床前研究支持这样一种概念，即更倾向于心血管表型的供体细胞有利于修复。基于这一理念，我们之前发现组蛋白去乙酰化酶 1（HDAC1）是心脏间充质细胞（CMC）体外成心肌谱系定向和旁分泌信号转导能力的介质，提示 HDAC1 可能是增强 CMC 心脏修复能力的潜在治疗靶点。在本研究中，我们使用苯甲酰胺类 1 型选择性 HDAC 抑制剂恩替诺特（entinostat，MS-275）研究了药物抑制 HDAC1 对 CMC 成心肌谱系定向和 CMC 介导的心肌修复的影响。在再灌注心肌梗死 30 天后，将用恩替诺特或 DMSO 稀释剂对照预处理的人 CMC 心肌内注射到慢性缺血性心肌病的裸鼠模型中。治疗 35 天后，通过超声心动图和左心室（LV）Millar 导引导管测量评估心脏功能指标。与未处理的 CMC 相比，恩替诺特处理的 CMC 在体外具有更高的肌样细胞分化能力，并且在体内具有更好的减轻 LV 重构和收缩功能障碍的能力。与未处理的 CMC 相比，恩替诺特预处理提高了 CMC 的治疗效果，但这与增强供体细胞移植、心肌生成或血管生成无关，而是与更有效的心肌纤维化抑制和更大的心肌细胞大小增加有关。这些结果表明，HDAC 抑制增强了 CMC 的修复能力，可能通过改善心室顺应性和收缩性以及增加心肌细胞生长和功能的旁分泌机制。
