抑制HDAC可以逆转先前存在的透气功能障碍,并阻止隐藏的细胞外基质重塑
Joshua G Travers1,2, Sara A Wennersten1,2, Brisa Peña1,2
1Department of Medicine, Division of Cardiology (J.G.T., S.A.W., B.P., R.A.B., Y.-H.L., K.M.D.-D., M.A.C., L.M., K.C.W., M.P.Y.L., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora.
Circulation
|March 8, 2021
概括
通过阻断细胞外矩阵扩张和降低心脏硬度,抑制基因脱甲基酶 (HDAC) 逆转了已存在的透气功能障碍 (DD). 这种治疗方法提供了一种新的心力衰竭治疗策略,
科学领域:
- 心血管医学
- 分子生物学
- 药理学
背景情况:
- 腹筋功能障碍 (DD) 是心力衰竭和心房的发病的一个关键因素.
- 通过改善肌纤维放松, 素脱乙酶 (HDAC) 抑制在预防DD方面表现有前途.
- 这项研究研究了HDAC抑制在已确定的DD与保存的射出分数的治疗潜力.
研究的目的:
- 评估临床阶段的HDAC抑制剂ITF2357/Givinostat在已确诊的腹筋功能障碍的小鼠模型中的疗效.
- 在此模型中阐明HDAC抑制对心脏结构和功能的机制.
主要方法:
- 在小鼠中通过无切除和脱氧皮质颗粒植入确立的腹功能障碍.
- 使用ITF2357/Givinostat进行心脏功能评估,使用心声学,血液动力学分析和ex vivo肌纤维机制.
- 使用先进显微镜,质谱和原子力显微镜评估心脏纤维化,细胞外基质蛋白表达和左心室硬.
主要成果:
- 在不影响血压的情况下,HDAC抑制使腹功能正常化.
- 虽然传统的纤维化标志物不存在,但质谱检测显示显著的细胞外矩阵扩张和左心室硬度增加.
- 通过抑制心脏纤维细胞激活,ITF2357/Givinostat治疗有效抑制了细胞外矩阵扩张和心脏硬度的降低.
结论:
- 通过抑制HDAC,可以扭转现有的扩张功能障碍.
- 阻断细胞外矩阵重塑代表了HDAC抑制剂改善心室填充的新机制.
- 这项研究强调了"隐藏"的心肌纤维化的存在以及检测它的各种方法的必要性.
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