New Insight in HDACs: Potential Therapeutic Targets for the Treatment of Atherosclerosis

Abstract

Atherosclerosis (AS) features include progressive hardening and reduced elasticity of arteries. AS is the leading cause of morbidity and mortality. An increasing amount of evidence showed that epigenetic modifications on genes serve are a main cause of several diseases, including AS. Histone deacetylases (HDACs) promote the deacetylation at lysine residues, thereby condensing the chromatin structures and further inhibiting the transcription of downstream genes. HDACs widely affect various physiological and pathological processes through transcriptional regulation or deacetylation of other non-histone proteins. In recent years, the role of HDACs in vascular systems has been revealed, and their effects on atherosclerosis have been widely reported. In this review, we discuss the members of HDACs in vascular systems, determine the diverse roles of HDACs in AS, and reveal the effects of HDAC inhibitors on AS progression. We provide new insights into the potential of HDAC inhibitors as drugs for AS treatment.

Keywords: HDAC inhibitors; atherosclerosis (AS); deacetylation; histone deacetylases (HDACs); vascular systems.

FIGURE 1

Classification and sublocation of HDACs. HDACs can be classified into Class I, II, III, and IV according to similarities. Class I HDACs (HDAC1/2/3/8) are mostly located in the nucleus. Class II HDACs are subclassified into subclass IIa (HDAC4, 5, 7 and 9) and subclass IIb (HDAC6 and 10). Class IIa HDACs translocate between cytoplasm and nucleus. Class IIb members mostly localize in the cytoplasm. Class III contains seven members (SIRT1 to 7). SIRT1/2 shuttle between the nucleus and cytoplasm. SIRT6/7 are mostly in the nucleus. SIRT3/4/5 are localized in the mitochondria. Class IV HDAC (HDAC11) is predominantly located in the nucleus.

FIGURE 2

The function of HDACs in ECs, SMC, and macrophages. The alteration of proliferation, migration, and apoptosis of ECs and SMCs is indispensable in AS. HDAC1/2/3/7 regulate SMC proliferation. HDAC3/4/7 are involved in SMC migration. HDAC3/5 modulate inflammation in macrophage. HDAC3/9 regulate proinflammatory gene expression by modulating M2 macrophage polarization. HDAC11 plays a critical role in vascular injury. SIRT1 is directly related to EC senescence and apoptosis. SIRT6 protects EC from senescence. HDAC1/2/3 are reportedly involved in EC proliferation mediated by oscillatory shear stress. In addition, HDAC5 represses angiogenesis in ECs.

FIGURE 3

Diverse functions of HDACs in blood vessels. HDACs are widely involved in the cellular processes in blood vessels, such as cell proliferation, migration, and differentiation. HDAC1/2/3/4/5/6/7 and SIRT1/3/6/7 are involved in cell proliferation. HDAC1/3/4/5/6/7 and SIRT1/3/6/7 regulate cell migration. HDAC1/3/4/6/9 and SIRT1/2/3/6 mediate cell apoptosis. HDAC1/2/3/4/5/6/7/8/9/11 and SIRT2/3/4/6/7 modulate inflammation. HDAC1/2/3/4/5/6/7/9 and SIRT1/2/3/6 modulate angiogenesis. HDAC3/6 and SIRT1/6 modulate cell apoptosis. HDAC2/3/6 and SIRT3/6 are associated with oxidative stress. HDAC1/2/3/5/6 and SIRT2 are associated with NO production. HDAC1/4/9 and SIRT1/3/6 modulate cell autophagy.

FIGURE 4

The potential mechanism of HDACs in atherosclerosis. SIRT1 and SIRT6 perturbation promotes cholesterol efflux by activating ABCA1 and ABCG1, leading to reduced macrophage-derived foam cell formation. Deacetylation of ATG5 by SIRT1 activates ATG5 to increase autophagy, which protects from AS. SIRT1-mediated deacetylation of cortactin promotes the translocation of cortactin to the cell periphery, whereas its interaction with cortical actin activates eNOS under shear stress conditions, which increases the bioavailability of nitric oxide (NO) and protects from AS. HDAC3/9 are stimulated in response to monocyte differentiation to macrophages in LDLR ^−/− mice kept on an atherogenic diet. HDAC6 is implicated in the prevention of endothelial injury and AS. NO bioavailability is increased by SIRT1-mediated deacetylation of eNOS and decreased by HDAC3-mediated deacetylation of eNOS. Acetylation of NF-κB subunits activates the expressions of Nos1, Nos2, and pro-inflammatory genes. High levels of NO and oxidative stress promote AS.