To date, studies have indicated that there is a strong association between diabetes and heart failure. Diabetes mellitus (DM) is one of the most common risk factors for the development of non-ischemic heart failure, and its identification results in the initiation of cardioprotective therapy (1). Therefore, cardiovascular complications constitute the main cause of morbidity and mortality in diabetic patients. In total, 80% of related deaths occur due to cardiovascular diseases in these patients (2). These complications include atherosclerosis, coronary artery disease, and myocardial infarction (3). Diabetic cardiomyopathy (DCM), is another cardiac disorder caused by diabetes (4).

DCM is defined as a heart disorder of a diabetic patient in which abnormal myocardial structures, such as coronary lesions, valvular heart disease and hypertension are absent. This disorder is characterized by diastolic or systolic dysfunction, combined with structural changes, such as fibrosis and hypertrophy (5). The pathophysiology of DCM is complex and involves various mechanisms, such as inflammation, mitochondrial dysfunction, apoptosis, oxidative stress, lipotoxicity, fibrosis and disruptions in insulin signaling (6). Even though extensive research has been conducted concerning diabetic cardiovascular disorders, the efficacy of treatment remains a challenge (7,8).

Multiple contributing mechanisms are associated with diabetic heart disease. It is well established that hyperglycemia plays a critical role in diabetes-related heart failure (9,10). Following a protein modification mechanism and the induction of epigenetic alterations, as well as mitochondrial damage, hyperglycemia results in myocardial dysfunction. Oxidative stress is also associated with both non-cardiac and cardiac diabetes-related complications. Oxidative stress usually provokes impaired cardiomyocyte calcium handling and leads to reduced cardiac contractility and relaxation. Inflammation is another mechanism that leads to the progression of diabetes. Increased inflammatory signaling often results in macrophage infiltration and thus, in cardiac DM-related complications (9).

Moreover, autonomic dysfunction has an impact on myocardial performance, and systemic and coronary vascular function (11). Autonomic dysfunction is a significant complication of DM that is firmly linked to a roughly five-fold increased risk of cardiovascular mortality. Its presentation ranges from resting tachycardia and a fixed heart rate to the development of silent myocardial infarction (12).

Consequently, myocardial hypertrophy, fibrosis and myocardial dysfunction lead to the progression of heart failure. Cardiac complications, such as disrupted insulin signaling, the renin-angiotensin-aldosterone system, and small and large-vessel disease lead to alterations in myocardial energetics, cardiac remodeling and impaired perfusion (11). Myocardial energy depletion in individuals suffering from DM is multifactorial and is associated with limitations in the uptake and utilization of substrates, mitochondrial dysfunction and affected energy transfer from mitochondria to myofibrils. These metabolic alterations combined with affected myocardial perfusion, may result in the reduced ability of the heart to cope with acute increases in workload (13).

As a result, myocardial dysfunction, cardiac stiffness and myocardial fibrosis occur. Finally, cytosolic calcium trafficking and gene expression cause excitation-contraction decoupling, and lead to cardiomyocyte contraction and relaxation (11).

Histone deacetylases (HDACs) are enzymes that exert their activities through the alteration of chromatin regulation. The balance between HDACs and histone acetyltransferases (HATs) controls that regulation. As their name suggests, they remove acetyl-groups from histones. They actually regulate the interaction between the negatively charged DNA and positively charged histones. Thus, they serve as a repressor of transcription (14) (Fig. 1). The 18 HDACs are divided into four classes as follows: The class I Rpd3-like proteins (HDAC1, HDAC2, HDAC3 and HDAC8); the class II Hda1-like proteins (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10); the class III Sir2-like proteins [sirtuin (SIRT)1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7]; and the class IV protein (HDAC11) (15).

The HDACs of classes I, II and IV exhibit a zinc-dependent activity. On the contrary, class III HDACs or SIRTs (SIRT1-7) require nicotinamide adenine dinucleotide (NAD) for catalysis (Table I) (14). Their crucial roles in epigenetics and gene expression have rendered them potential targets in various diseases, including both metabolic and cardiovascular entities (16).

HDAC inhibitors (HDACIs) are already used as anticancer agents. Of note, four of them have already been approved by the US Food and Drug Administration (FDA) against hematological malignancies (14). Additionally, their anticancer activity has been reported extensively in the literature, including colorectal, hepatocellular, pancreatic, breast, thyroid, lung, endometrial, and other cancers such as uveal and cutaneous melanoma (17-27). Furthermore, their role appear to be crucial in fighting other diseases, including viral infections and both inflammatory and neurological disorders (28,29). Hyperglycemia is a crucial factor that contributes to the development of oxidative stress, mitochondrial injury, reactive oxygen species (ROS) and myocardial inflammation (30,31). Thus, HDACIs appear to be promising therapeutic agents against cardiovascular diseases, including DCM.

The present review article reports pre-clinical trials identified in which HDACIs were tested in animal models of DCM. The roles and mechanisms of action of HDACIs in metabolic and cardiovascular diseases were also discussed.

In 2015, Chen et al (31) examined the role of sodium butyrate, which is a specific HDACI, in preventing myocardial dysfunction in diabetic mice. They established a model of diabetes using mice by injecting the mice intraperitoneally with streptozocin. The next step was the administration of sodium butyrate to certain subgroups of these mice. The echocardiography findings revealed that cardiac dysfunction was attenuated in he diabetic mice receiving sodium butyrate. Additionally, the attenuation of cardiac remodeling and interstitial fibrosis were noted. These findings were associated with an increase in cardiac angiogenesis, and a decrease in both apoptosis and active caspase 3. Glucose metabolism was improved through the upregulation of glucose transporter (GLUT)-1 and -4. Finally, sodium butyrate exerted an antioxidant effect on the myocardium by elevating superoxide dismutase levels (31).

Lee et al (32,33) conducted research on diabetic rats who received low doses of streptozocin. MPT0E014, which is a pan-HDACI, was administered to a subgroup of diabetic rats. The left-ventricular end-diastolic diameter was smaller in the diabetic rats receiving the HDACI compared to the diabetic rats not receiving the treatment. The reduction in blood sugar and triglyceride levels revealed the anti-hyperglycemic and hypolipidemic effects of MPT0E014. At the cellular level, GLUT-4 expression was augmented through HDACI administration via an insulin-independent pathway. The cleavage of poly(ADP-ribose) polymerase 1 (PARP-1) was decreased, inhibiting apoptosis. The levels of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) or interleukin (IL)-6 were reduced following treatment with MPT0E014(32). Finally, the procedure of autophagy, which is necessary for the development and homeostasis of cells, was accelerated following the administration of this HDACI (33).

Wu et al (34) investigated whether the suppression of HDACs in diabetic rat hearts could protect the rats from myocardial ischemia/reperfusion (MI/R) injury mediated via the PI3K/Akt pathway (34). This pathway results in the activation of anti-apoptotic proteins that inhibit mitochondrial dysfunction during MI/R injury (34,35). In their experiment, diabetic rats underwent 45 min of ischemia followed by 3 h of reperfusion. They used trichostatin A (TSA), a selective I and II HDACI, both in vitro and in vivo experiments. Their study was the first to demonstrate that MI/R injury and diabetes increased HDAC activity in rat hearts. However, TSA protected the function and integrity of mitochondria both in vivo and in vitro through the expression of p-Akt via the increased phosphorylation of p-Foxo3a and Foxo3a in the cytoplasm of myocardial cells (34).

Leng et al (36) used the same methods and experimental model as those in the study by Wu et al (34); however, they concentrated on the inhibition of HDAC6 activity using tubastatin A (Tub A), a highly selective HDAC6 inhibitor. Their research demonstrated that both in vivo and in vitro, Tub A exhibited its cardioprotective actions in diabetic rat hearts by modulating peroxiredoxin 1 (Prdx1) acetylation and attenuating ROS generation and subsequent cellular injury (36).

Another group of researchers examined the association between the inhibition of HDAC3 and DCM. RGFP966, a selective HDAC3 inhibitor, and valproic acid were administered to mice with type 1 diabetes (37). Treatment with RGFP966 prevented cardiac hypertrophy through various mechanisms. Firstly, a reduction in heart hypertrophy and fibrosis markers was noted. Histologically, cardiomyocyte size, fibrosis and the accumulation of collagen were suppressed. Insulin resistance, oxidative stress and inflammatory processes were all diminished. TNF-α, plasminogen activator inhibitor-1 and ROS production were downregulated, whereas the expression of GLUT-4 was upregulated. The dual specificity phosphatase 5 (DUSP5), which is an extracellular signal-regulated kinase 1 and 2 (ERK1/2) nuclear phosphatase, inhibits phosphorylated extracellular signal-regulated kinases ERK1/2, which accelerates cardiac hypertrophy (37). The administration of RGFP966 exerted its cardioprotective effects through an increase in the levels of DUSP5. Last but not least, they demonstrated that these effects lasted for a period of time, since the protective activity of RGFP966 remained for 3 months after the end of its administration (37).

Zhang et al (7) performed a study in which they administered sodium butyrate to mice with type 2 diabetes. Treatment with sodium butyrate reduced obesity, hypercholesterolemia, and glucose intolerance. In addition, the wall thickness and the internal dimension of the left ventricle were smaller in the diabetic group treated with sodium butyrate, compared with the untreated diabetic group. Both the size of the cardiomyocytes and collagen presence were limited in the mice receiving the HDACI. The production of superoxide and active caspase-3, which is an apoptotic agent, were significantly reduced. Angiogenesis and capillary formation were enhanced using sodium butyrate. Finally, sodium butyrate can activate signaling pathways, such as mitogen-activated protein kinase 3 (MKK3)/p38/regulated-activated kinase (PRAK) and Akt-1, in order to regulate proper cardiac function (7).

Bocchi et al (38) reported the action of suberoylanilide hydroxamic acid (SAHA), a pan-HDACI, in the cardiomyocytes of diabetic rats. Ventricular cardiomyocytes were extracted in order to measure their contractility and calcium dynamics. These cells were either treated with SAHA for 90 min or left untreated. The group treated with SAHA exhibited higher contractility and calcium dynamics. This was a result of the upregulation in ryanodine receptors and a decrease in intracellular ROS levels (38).

Table II summarizes the findings of all the aforementioned studies reporting the potential role of HDACIs against DCM in experimental models (5,31-34,36-38).

HDACIs are divided according to their actions on HDACs. They are divided into hydroxamic acids, short-chain fatty acids, cyclic peptides and benzamides. They are mostly studied and used against malignancies (8). However, extensive research into the possible therapeutic effects of HDACIs on DCM has been performed (5,31-34,36-38). HDAsC contribute to the development of DCM through various metabolic and hypertrophic pathways (39).

The inhibition of HDACs prevents cardiac hypertrophy a number of mechanisms. As described above, active caspase-3 is a protein which triggers apoptosis. The anti-apoptotic effects of HDACIs are demonstrated through the reduction of apoptosis (31). The inflammatory process is reduced through the downregulation of pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6 and IFN-γ (40). Angiogenesis is accomplished through the increased production of vascular endothelial growth factor (VEGF) (41). The reduction of ROS generation diminishes oxidative stress (37) and can be accomplished by the modulation of acetylation of Prdx1(36). Autophagy is an adaptive mechanism, whose absence induces intracellular death (42). As Lee et al (32,33) demonstrated, HDACIs can increase autophagy and protect the myocardium. Wu et al (34) demonstrated that the protection of the function of mitochondria via the regulation of P13K/Akt expression decreased cell apoptosis and protected the diabetic heart. The transcription of GLUT-4 is regulated by class II HDAC in skeletal muscles (43,44). The upregulation of GLUT by HDACIs leads to the entrance of glucose into cells and to a reduction in both insulin resistance and hyperglycemia (32,45). Fibrosis is reduced by inhibiting TGF-β and the angiotensin type 2 receptor (46). The mechanisms of action of HDACIσ against DCM are reported in Table III and are illustrated in Fig. 2.

Conventionally, HDACIs are considered as anticancer drugs. However, they appear to be useful in the treatment of other non-malignant diseases. The present review article reported numerous preclinical trials, which examined the association between HDACs, HDACIs and DCM. The use of HDACIs has yielded encouraging results against disease progression. Research has markedly enhance current knowledge on HDACs and their roles in metabolic and cardiovascular dysfunction. Additionally, HDACs are considered as possible therapeutic targets against heart failure in general. Due to the novelty of this approach, further research into the mechanisms of action and biochemical pathways of HDACs and their inhibitors is warranted prior to any clinical applications. Extending current knowledge regarding the therapeutic potential of HDACIs against these diseases will pave the way for the discovery of novel targeted epigenetic drugs. Thus, millions of individuals will be beneficially affected worldwide in the future.