Zinc-dependent histone deacetylases: Potential therapeutic targets for arterial hypertension.

The pathogenesis of hypertension caused by various genetic and environmental factors has not been elucidated. Clinical trials have evaluated various anti-hypertensive drugs with different therapeutic mechanisms. Due to the increasing prevalence of hypertension in the aging population and appearance of adverse effects, novel anti-hypertensive drugs need be developed. Histone deacetylases (HDACs), a group of enzymes which have recently attracted attention, are dysregulated in several cancers and cardiovascular diseases. Mammalian HDACs are categorized into four classes: class I HDAC (HDAC1, 2, 3, 8), class IIa HDAC (HDAC4, 5, 7, 9), class IIb HDAC (HDAC6, 10), and class IV HDAC (HDAC11) are zinc-dependent enzymes, while class III HDACs are nicotinamide adenine dinucleotide (NAD)-dependent enzymes. In this review, we focused on the pharmacological inhibitors of zinc-dependent HDACs used for controlling hypertension. We addressed the biological effects and underlying mechanisms of isoform-selective, class HDAC-selective, or pan-HDAC inhibitors on various hypertensive animal models (angiotensin II infusion mice, deoxycorticosterone acetate-salt-induced rats, spontaneously hypertensive rats, high-fat diet-treated mice, and nitric oxide (NO)-deficient mice) and HDAC5 deletion mice. We discuss the cardiovascular phenotypes of class I and IIa/b HDAC-deficient mice and potential adverse effects of HDAC inhibitors in preclinical studies. This review summarizes recent studies on synthetic or dietary HDAC inhibitors (sulforaphane, gallic acid, and curcumin) that alleviate hypertension by the regulating renin-angiotensin-aldosterone system, vascular hypertrophy, vasoconstriction, inflammation, or oxidative stress. Although the phenotypic analysis of hypertension in isoform HDAC deletion mice is required, few HDACs (HDAC3, HDAC4, and HDAC8) are promising therapeutic targets for treating hypertension.

Dendropanax morbifera Prevents Cardiomyocyte Hypertrophy by Inhibiting the Sp1/GATA4 Pathway.

An extract of Dendropanax morbifera branch exerts antioxidant, anti-inflammatory, antithrombotic, and anticancer activities. The purpose of this study was to investigate the effect of the extract in isoproterenol-induced cardiac hypertrophy. Phalloidin staining showed that treatment with the extract dramatically prevents isoproterenol-induced H9c2 cell enlargement and the expression of cardiac hypertrophic marker genes, including atrial natriuretic peptide (ANP) and B-type brain natriuretic peptide (BNP). Further, pretreatment with the extract decreased isoproterenol-induced GATA4 and Sp1 expression in H9c2 cells. Overexpression of Sp1 induced the expression of GATA4. The forced expression of Sp1 or its downstream target GATA4, as well as the co-transfection of Sp1 and GATA4 increased the expression of ANP, which was decreased by treatment with the extract. To further elucidate the regulation of the Sp1/GATA4-mediated expression of ANP, knockdown experiments were performed. Transfection with small interfering RNAs (siRNAs) for Sp1 or GATA4 decreased ANP expression. The extract did not further inhibit the expression of ANP reduced by the transfection of GATA4 siRNA. Sp1 knockdown did not affect the expression of ANP that was induced by the overexpression of GATA4; however, GATA4 knockdown abolished the expression of ANP that had been induced by Sp1 overexpression. The extract treatment also attenuated the isoproterenol-induced activation of p38 MAPK, ERK1/2, and JNK1. Hesperidin, catechin, 2,5-dihydroxybenzoic acid, and salicylic acid are the main phenolic compounds present in the extract as observed by high performance liquid chromatography. Hesperidin and 2,5-dihydroxybenzoic acid attenuated isoproterenol-induced cardiac hypertrophy. These findings suggest that the D. morbifera branch extract prevents cardiac hypertrophy by downregulating the activation of Sp1/GATA4 and MAPK signaling pathways.

Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding.

BACKGROUND: A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure. Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB). METHODS AND RESULTS: Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, alpha-tubulin, beta-myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition. CONCLUSIONS: These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.