Department of Regenerative medicine, State Research Institute Centre for Innovative Medicine, LT 08406 Vilnius, Lithuania.
Centre of Cardiothoracic Surgery of Vilnius University Hospital Santariskiu Clinic, LT 08406 Vilnius, Lithuania.
Int J Mol Sci. 2020 Jul 8;21(14):4845. doi: 10.3390/ijms21144845.
In this study the effect of histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on the energetic status and cardiomyogenic differentiation of human healthy and dilated myocardium-derived mesenchymal stromal cells (hmMSC) have been investigated.
The hmMSC were isolated from the healthy and dilated post-operation heart biopsies by explant outgrowth method. Cell proliferation, HDAC activity, mitochondrial membrane potential, and level of adenosine triphosphate (ATP) were evaluated. The effect of SAHA on mitochondrial parameters has been investigated also by Seahorse XF analyzer and cardiomyogenic differentiation was confirmed by the expression of transcription factor NK2 Homeobox 5 (Nkx2.5), cardiac troponin T and alpha cardiac actin at gene and protein levels.
Dilated myocardium-derived hmMSC had almost 1.5 folds higher HDAC activity compared to the healthy cells and significantly lower mitochondrial membrane potential and ATP level. HDAC class I and II inhibitor SAHA improved energetic status of mitochondria in dilated myocardium-isolated hmMSC and increased expression of cardiac specific proteins during 14 days of exposure of cells to SAHA.
HDAC inhibitor SAHA can be a promising therapeutic for dilated cardiomyopathy (DCM). Dilated hmMSC exposed to SAHA improved energetic status and, subsequently, cardiomyogenic differentiation. Data suggest that human dilated myocardium-derived MSC still have cardio tissue regenerative potential, which might be stimulated by HDAC inhibitors.
在这项研究中，研究了组蛋白去乙酰化酶（HDAC）抑制剂 suberoylanilide hydroxamic acid（SAHA）对健康和扩张型心肌病来源的间充质基质细胞（hmMSC）的能量状态和心肌发生分化的影响。
通过组织块培养法从健康和扩张型术后心脏活检中分离 hmMSC。评估细胞增殖、HDAC 活性、线粒体膜电位和三磷酸腺苷（ATP）水平。还通过 Seahorse XF 分析仪研究了 SAHA 对线粒体参数的影响，通过转录因子 NK2 Homeobox 5（Nkx2.5）、心肌肌钙蛋白 T 和α心脏肌动蛋白的基因和蛋白水平的表达来确认心肌发生分化。
与健康细胞相比，扩张型心肌来源的 hmMSC 的 HDAC 活性高近 1.5 倍，线粒体膜电位和 ATP 水平明显降低。HDAC 类 I 和 II 抑制剂 SAHA 改善了扩张型心肌分离的 hmMSC 中线粒体的能量状态，并在细胞暴露于 SAHA 的 14 天内增加了心脏特异性蛋白的表达。
HDAC 抑制剂 SAHA 可能是扩张型心肌病（DCM）的一种有前途的治疗方法。暴露于 SAHA 的扩张型 hmMSC 改善了能量状态，随后促进了心肌发生分化。数据表明，人类扩张型心肌来源的 MSC 仍然具有心脏组织再生的潜力，这可能受到 HDAC 抑制剂的刺激。
