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Int. J. Mol. Sci. 2019, 20(8), 1873; https://doi.org/10.3390/ijms20081873

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

1
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy
2
Institute for Biomedicine, Eurac Research, 39100 Bolzano, Italy (affiliated institute of the University of Lübeck, 23562 Lübeck, Germany)
3
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 16 March 2019 / Revised: 9 April 2019 / Accepted: 12 April 2019 / Published: 16 April 2019
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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Abstract

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. View Full-Text
Keywords: diabetes; HDAC inhibition; cardiomyocyte mechanics; calcium transients; cell oxidative stress diabetes; HDAC inhibition; cardiomyocyte mechanics; calcium transients; cell oxidative stress
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Bocchi, L.; Motta, B.M.; Savi, M.; Vilella, R.; Meraviglia, V.; Rizzi, F.; Galati, S.; Buschini, A.; Lazzaretti, M.; Pramstaller, P.P.; Rossini, A.; Stilli, D. The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Restores Cardiomyocyte Contractility in a Rat Model of Early Diabetes. Int. J. Mol. Sci. 2019, 20, 1873.

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