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.
Highlights
Diabetes is a risk factor for the development of various cardiovascular complications, which constitute the leading causes of morbidity and mortality in both type 1 and type 2 diabetic subjects [1]
Ex-vivo experiments were performed to evaluate the ability of suberoylanilide hydroxamic acid (SAHA) exposure to ameliorate calcium dynamics and contractile properties of CMs isolated from adult rats after a short period of hyperglycemia (3 weeks) that constitutes a time point characterized by the occurrence of the first signs of dysfunction, as measured at the cellular level [4]
Slower calcium kinetics were observed in D cells, which exhibited a prolonged time-to-peak of the calcium transient (TTP, +19%, p < 0.01, Figure 1D) associated with higher values of the time required for cytosolic calcium clearing, in the absence of statistically significant differences in the amplitude of the calcium transient (F/F0, fold increase) that showed only a slight decrease (−9%, Figure 1C)
Summary
Diabetes is a risk factor for the development of various cardiovascular complications, which constitute the leading causes of morbidity and mortality in both type 1 and type 2 diabetic subjects [1]. Hyperglycemia is a central player in activating several adaptive and maladaptive responses in myocardial tissue among which cell oxidative stress and moderate tissue inflammation constitute critical early pathogenic components [4,5,6,7,8,9]. Mitochondrial injury has a causative role in the pathophysiology of diabetic heart disease [5,10], largely contributing to the generation of reactive oxygen species (ROS) and myocardial inflammation, leading to the development and progression of cardiac abnormalities and dysfunction. There is a need to identify novel adjuvant therapeutic approaches aimed at counteracting the initial hyperglycemia-induced alterations in myocardial tissue
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