Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Improves Energetic Status and Cardiomyogenic Differentiation of Human Dilated Myocardium-Derived Primary Mesenchymal Cells

Abstract

<jats:p>Background. 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. Methods. 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. Results. 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. Conclusions. 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.</jats:p>

Cardiomyogenic Differentiation Potential of Human Dilated Myocardium-Derived Mesenchymal Stem/Stromal Cells: The Impact of HDAC Inhibitor SAHA and Biomimetic Matrices

“…In addition, the MSC isolated from different types of adult tissues can have specific features: human fetal heart MSC was shown to have cardiac immunophenotyping and differentiation potential to CM, endothelial, or smooth muscle cells [ 42 , 43 , 44 ]. Human heart myocardium-derived MSCs can be used to investigate the human heart pathologies and/or possible ways of heart regeneration [ 45 , 46 ]. Other authors also suggested that adult human heart tissue-derived MSC have better cardio regenerating capabilities compared to the bone marrow or other types of adult MSC [ 47 ].…”

“…In previous studies, SAHA has been clinically approved for the treatment of cutaneous T-cell lymphoma (CTCL) and was shown to exert anticancer activities in various other types of tumors [ 58 ]. In addition, recent our publication showed SAHA suppressing HDAC1 and HDAC2 expression in dilated myocardium-derived MSC, improved mitochondrial activity and energetic status of human dilated myocardium-derived hmMSC [ 46 ]. Similar findings also confirmed HDAC1 and HDAC2 being the main regulators of histone acetylation [ 59 ].…”

“…The MSC origin of human healthy and dilated myocardium-derived MSC (hmMSC) has been investigated as described elsewhere [ 43 , 46 ]. Briefly, cell growth media was aspired, washed with PBS and exposed to 0.25% trypsin-EDTA (Thermo Fisher Scientific, Waltham, MA, USA) for 1–2 min.…”

The Emerging Role of Epigenetics in Therapeutic Targeting of Cardiomyopathies

“…Murine models of HDAC1 and HDAC2 knockouts presented with dilated cardiomyopathy phenotypes, resulting from, among other factors, an upregulation of gene expression related to contractile proteins and calcium channels [50]. A recent study showed that the use of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) promoted cardiomyogenic differentiation; in the context of DCM, this could be a very promising therapeutic target for activating the regenerative potential of hmMSCs (myocardium-derived mesenchymal stem cells) in the dilated myocardium [51]. One study outlined a potential role of the histone acetyltransferase EP300 in the regulation of the myosin binding protein C cardiac isoform (MYBPC3), which is a thick filament accessory protein of the striated muscle sarcomere A band.…”

Cell Programming for Cardiovascular Disease Modeling and Therapy

“…Human mesenchymal stromal cells (hmMSC) from healthy and dilated myocardium represent an interesting alternative cell source to generate cardiomyocytes for therapy as well as disease modeling. In their original article, Miksiunas et al investigated the effects of the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on energy metabolism and the cardiac differentiation of these cells [8]. In explant outgrowths, cell proliferation, HDAC activity, mitochondrial membrane potential and ATP levels were determined, as well as Nkx2.5, cardiac troponin T and α-actinin expression and mitochondrial activity.…”