Hypertension (HTN) is a major modifiable risk factor for cardiovascular disease. The left ventricle is the primary target of HTN related end-organ damage. In addition to being a marker of HTN, cardiac remodelling of left ventricle occur initially as compensatory responses to increased systemic pressure overload, which modifies the performance and changes the geometry of the heart. Blood pressure control with lifestyle changes and anti-hypertensive agents prevents and regresses left ventricular hypertrophy (LVH) [1, 2]. Furthermore, the relationship between HTN and renal disease is well-known. Although progression to end-stage renal disease is relatively low in uncomplicated essential HTN, mild renal dysfunction could occur, such as a subclinical end-organ damage in untreated patients with primary HTN. Thus, the presence of LVH could represent a relationship between renal failure and cardiovascular diseases in all stages of renal failure, starting from the earliest stage [3, 4].

Recent studies have suggested that the left ventricle remodelling begins much earlier than expected and is seen in normotensive patients with mild renal dysfunction when the glomerular filtration rate is still normal. Strategies to reduce LVH include lowering the blood pressure and reducing hypervolemia [5]. Numerous medications, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, and diuretics, have been shown to regress the blood pressure to normal levels. Nevertheless, numerous reports have raised concerns that these current existing medications do not reverse the remodelled heart to the previous normal physiology, which highlights the need of discovering new agents that can protect or reverse cardiac remodelling in conditions of hemodynamic pressure overload [1, 2, 6].

Various studies have shown that histone deacetylase (HDAC) inhibitors are effective in the treatment of cancer, autoimmune diseases, inflammatory diseases, interstitial fibrosis, cardiovascular diseases, and renal diseases [7, 8]. Our previous studies reported that valproic acid has cardiac and vascular protective effects [2] and mocetinostat attenuates aortic remodelling [9] in pressure overload-induced cardiac hypertrophy. Other reports have also reported the effects of numerous HDAC inhibitors in various animal models of cardiovascular or renal disease. Valproic acid [10, 11] and CG200475 [12] attenuate hypertrophy and fibrosis of the heart in DOCA-salt-induced hypertensive rats. Trichostatin A, valproic acid, and SK-7041 prevent hypertrophy of the heart in animal models of angiotensin II-infused cardiac hypertrophy [13]. Valproic acid ameliorates the angiotensinogen II production in the kidney in high-fat diet-induced HTN model [7]. Trichostatin A [14] and CG200745 [15] attenuate renal fibrosis in unilateral ureteral obstruction mouse model.

Mocetinostat (MGCD0103), is a chemical synthesised aminobenzamide class I (HDAC1, HDAC2, and HDAC3) or IV (HDAC11) HDAC inhibitor which widely inhibits HDAC1 and is oral route administeration. Studies have reported its anti-fibrotic capacities [9, 16, 17]. The transverse aortic constriction (TAC) animal model represents pressure overload cardiac hypertrophy by introducing LVH via the pressure of systemic HTN [18]. Our study proposed that the HDAC inhibitor, mocetinostat regulates cardiac remodelling and renin-angiotensin system (RAS) activity in rats with TAC-induced pressure overload cardiac hypertrophy.

In the current experiment, we presented that mocetinostat regulates cardiac remodelling and RAS activity in rats with TAC-induced pressure overload cardiac hypertrophy. The results demonstrated that mocetinostat administration regulated cardiac hypertrophy and fibrosis and correspondingly attenuated cardiac remodelling. It also regulated renal fibrosis and RAS activation during pressure overload.

Many reports have shown that HDAC inhibitors have cardioprotective or renoprotective effects in various animal models. The TAC-induced cardiac hypertrophic animal model mimics HTN or pressure overload in patients. HTN or pressure overload conditions, which cause cardiac hypertrophy, fibrosis, and remodelling, not only influences the heart, but also the kidney, resulting in mild renal dysfunction with normal serum creatine levels [3, 4]. Our study aimed to investigate the effect of HDAC inhibitors on the heart and kidney in a pressure overload animal model in order to identify a novel therapeutic agent to treat patients with HTN.

Hypertrophy of the heart is induced by systemic pressure overload in rat’s aorta via TAC; moreover, the gradually increasing pressure on the aorta may induce LVH as a consequential response to hemodynamic pressure and cause HTN [2, 9]. Our study was performed for four weeks, which was a relatively short period to develop left ventricular dysfunction or heart failure but long enough to induce LVH. LVH is characterised by thickened IVS and LVPW, increased left heart weight, cardiomyocyte hypertrophy, and increased gene expression of hypertrophy markers, such as Nppa and Nppb. Similar to previous studies [2, 9, 11, 12, 13], the above results also confirmed the cardioprotective effect of mocetinostat in pressure overload-induced LVH. In our study, mocetinostat treatment regressed IVS and LVPW, decreased left heart weight and cardiomyocyte size, and attenuated the gene expression of Nppa and Nppb (Figs. 2,3). As mocetinostat moderates the hypertrophy of the heart, hemodynamic pressure overload may reduce, and correspondingly decreases the blood pressure. This not only effects the systemic HTN but also the pulmonary HTN. Timothy A. McKinsey et al. [19] reported that mocetinostat possibly reduces the pulmonary artery pressure or the pulmonary HTN. In this study, rats were housed in hypobaric chambers to induce hypoxia, right ventricle hypertrophy, and pulmonary HTN. We assume that mocetinostat moderates the hypertrophy of the heart, either the left or right ventricle, depending on the animal model, and correspondingly decreases systemic or pulmonary HTN, respectively.

Fibrosis of the heart is characterised by collagen deposition and myocardial fibrosis. Fibrosis of the heart consequently increases with hypertrophy of the heart, resulting in left ventricular stiffness and cardiac remodelling [2]. HDAC inhibition diminishes cardiac myofibroblast activation and reduces cardiac fibrosis in a congestive heart failure animal model [20] and in rats with angiotensin II-infused heart dysfunction [6]. In the current study, mocetinostat attenuated histological fibrosis and expression of Collagen-1, Collagen-3, Ctgf, and Fibronectin mRNA (Fig. 4). Moreover, mocetinostat treatment suppressed left ventricular stiffness.

Chronic HTN, due to high blood pressure may induce mechanical shear stress along the aorta, heart, and kidneys and oxidative stress with chronic inflammation, and reparative mechanisms of these lead to end-organ damage, mainly fibrosis [21]. Kidney damage occurs along the entire course of HTN, ranging from benign to malignant form of nephropathy, relying on an individual’s susceptibility, level of HTN, type of aetiology, and underlying disease [22]. However, long-term HTN eventually results renal interstitial fibrosis, which activates renal fibroblasts and generates excessive deposition of extracellular matrix proteins. Moreover, tubular hypertrophy, oxidative stress, activation of the RAS, collagen turnover, chronic inflammation, and secretion of vasoactive substances synergistically contribute to the hypertensive renal fibrosis [23]. Several studies have reported the therapeutic capacity of HDAC inhibitors in various renal disease animal models. CG200745 attenuates renal fibrosis in a mouse model of obstructive kidney disease [15] and high-fat diet-induced HTN [7], and valproic acid ameliorates renal fibrosis in diabetic rats [24]. We treated TAC-induced pressure overload HTN rats with mocetinostat, an HDAC inhibitor. Mocetinostat attenuated histological fibrotic changes and the mRNA level of Collagen-1, Collagen-3, Ctgf, and Fibronectin, which were increased via pressure overload cardiac hypertrophy (Fig. 5). Classically, the kidney has an auto-regulatory mechanism (glomerular afferent arteriole contraction and tubuloglomerular feedback) to protect itself from sudden increase in blood pressure [22]. RAS is the most important and well-known hormonal system in controlling the blood pressure. HTN occurs by increased resistance of blood vessels and relates to the structural changes of the blood vessels. Angiotensin II is a vasoconstrictor hormone, which induces vascular remodelling and inflammations in the arteries in the heart and kidney [25, 26]. Components of the RAS importantly function to control the blood pressure, but they are also associated with the onset of HTN. Due to these functions, there have been attempts to identify new drugs targeting RAS components [21]. We investigated the serum concentration (renin, angiotensin II, and aldosterone) and mRNA expression (Renin and Agtr1) of the RAS components. In our study, mocetinostat treatment reduced the serum concentration of renin, angiotensin II, and aldosterone, suggesting that the HDAC inhibitor suppressed the RAS and eventually decreased the blood pressure (Fig. 6).

The current study has a few limitations. First, the detailed molecular signalling pathway of mocetinostat in regulating cardiac remodelling and RAS activity need to be further explored in the further investigation. Second, the clinical importance of mocetinostat must be studied in patients with HTN-related diseases.

In conclusion, the present study revealed that mocetinostat, an HDAC inhibitor, restores left ventricular remodelling, attenuates serum RAS components, and regulates the increased mRNA levels associated with cardiac hypertrophy (Nppa and Nppb), fibrosis (Collagen-1, Collagen-3, Ctgf, and Fibronectin), and RAS components (Renin and Agtr1). Therefore, mocetinostat has cardiorenal protective effects in TAC-induced pressure overload cardiac hypertrophy rats.

HDAC, histone deacetylase; HTN, hypertension; IVS, interventricular septum; LVH, left ventricular hypertrophy; LVPW, left ventricular posterior wall; RAS, renin-angiotensin system; TAC, transverse aortic constriction.

GJK, HJ, EL and SWC designed the experiment. HJ and EL conducted the experiment and collected the data. GJK, HJ and EL analysed the data and wrote the manuscript. HJ, EL and SWC edited the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Institutional Review Board of Kyungpook National University approved the animal experiment (Approval number: KNU2018-79). The animal experiment was conducted as per the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.