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.