Kee Hae Jin, Kim Inkyeom, Jeong Myung Ho
Heart Research Center of Chonnam National University Hospital, Gwangju 61469, Republic of Korea; Hypertension Heart Failure Research Center, Chonnam National University Hospital, Gwangju 61469, Republic of Korea.
Department of Pharmacology, Cardiovascular Research Institute, BK21 Plus KNU Biomedical Convergence Program and Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
Biochem Pharmacol. 2022 Aug;202:115111. doi: 10.1016/j.bcp.2022.115111. Epub 2022 May 28.
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.
由各种遗传和环境因素引起的高血压发病机制尚未阐明。临床试验评估了具有不同治疗机制的各种抗高血压药物。由于高血压在老年人群中的患病率不断上升以及不良反应的出现，需要开发新型抗高血压药物。组蛋白去乙酰化酶（HDACs）是最近受到关注的一类酶，在几种癌症和心血管疾病中存在失调。哺乳动物HDACs分为四类：I类HDAC（HDAC1、2、3、8）、IIa类HDAC（HDAC4、5、7、9）、IIb类HDAC（HDAC6、10）和IV类HDAC（HDAC11）是锌依赖性酶，而III类HDACs是烟酰胺腺嘌呤二核苷酸（NAD）依赖性酶。在本综述中，我们重点关注用于控制高血压的锌依赖性HDACs的药理抑制剂。我们阐述了亚型选择性、HDAC类选择性或泛HDAC抑制剂对各种高血压动物模型（血管紧张素II输注小鼠、醋酸脱氧皮质酮盐诱导的大鼠、自发性高血压大鼠、高脂饮食处理的小鼠和一氧化氮（NO）缺乏小鼠）以及HDAC5基因敲除小鼠的生物学效应和潜在机制。我们讨论了I类和IIa/b类HDAC基因敲除小鼠的心血管表型以及HDAC抑制剂在临床前研究中的潜在不良反应。本综述总结了关于合成或膳食HDAC抑制剂（萝卜硫素、没食子酸和姜黄素）的最新研究，这些抑制剂通过调节肾素 - 血管紧张素 - 醛固酮系统、血管肥大、血管收缩、炎症或氧化应激来缓解高血压。尽管需要对亚型HDAC基因敲除小鼠的高血压进行表型分析，但很少有HDACs（HDAC3、HDAC4和HDAC8）是治疗高血压的有前景的治疗靶点。
