The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Restores Cardiomyocyte Contractility in a Rat Model of Early Diabetes

被引:13
|
作者
Bocchi, Leonardo [1 ]
Motta, Benedetta M. [2 ,3 ]
Savi, Monia [1 ]
Vilella, Rocchina [1 ]
Meraviglia, Viviana [2 ,3 ]
Rizzi, Federica [4 ]
Galati, Serena [1 ]
Buschini, Annamaria [1 ]
Lazzaretti, Mirca [1 ]
Pramstaller, Peter P. [2 ,3 ]
Rossini, Alessandra [2 ,3 ]
Stilli, Donatella [1 ]
机构
[1] Univ Parma, Dept Chem Life Sci & Environm Sustainabil, I-43124 Parma, Italy
[2] Eurac Res, Inst Biomed, I-39100 Bolzano, Italy
[3] Univ Lubeck, Inst Biomed, D-23562 Lubeck, Germany
[4] Univ Parma, Dept Med & Surg, I-43126 Parma, Italy
关键词
diabetes; HDAC inhibition; cardiomyocyte mechanics; calcium transients; cell oxidative stress; EPIGENETIC REGULATION; MECHANISMS; EXPRESSION; HYPERGLYCEMIA; CELLS;
D O I
10.3390/ijms20081873
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a crucial factor in the development of cardiac disorders. The present study evaluates whether HDAC inhibition can prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia, with focus on the potential underlying mechanisms. Cell contractility and calcium dynamics were measured in unloaded ventricular myocytes isolated from the heart of control and diabetic rats. Cardiomyocytes were either untreated or exposed to the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 90 min. Then, a fraction of each group of cells was used to evaluate the expression levels of proteins involved in the excitation-contraction coupling, and the cardiomyocyte metabolic activity, ATP content, and reactive oxygen species levels. SAHA treatment was able to counteract the initial functional derangement in cardiomyocytes by reducing cell oxidative damage. These findings suggest that early HDAC inhibition could be a promising adjuvant approach for preventing diabetes-induced cardiomyocyte oxidative damage, which triggers the pro-inflammatory signal cascade, mitochondrial damage, and ventricular dysfunction.
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页数:12
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