HDACs and Their Inhibitors on Post-Translational Modifications: The Regulation of Cardiovascular Disease

Abstract

Cardiovascular diseases (CVD), such as myocardial hypertrophy, heart failure, atherosclerosis, and myocardial ischemia/reperfusion (I/R) injury, are among the major threats to human health worldwide. Post-translational modifications alter the function of proteins through dynamic chemical modification after synthesis. This mechanism not only plays an important role in maintaining homeostasis and plays a crucial role in maintaining normal cardiovascular function, but is also closely related to the pathological state of various diseases. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression, and play important roles in post-translational modification by catalyzing the deacetylation of key lysine residues in nucleosomal histones, which are closely associated with the occurrence and development of cardiovascular diseases. Recent studies indicate that HDAC inhibitors (HDACis) may represent a new class of drugs for the treatment of cardiovascular diseases by influencing post-translational modifications. In this review, we systematically summarize the mechanism of action of HDACs and HDACis in post-translational modifications related to common cardiovascular diseases, providing new ideas for the treatment of CVD, and explore possible future research directions on the relationship between HDAC and HDACi in post-translational modifications and cardiovascular diseases.

Keywords: HDAC; HDACi; cardiovascular disease (CVD); post-translational modification (PTM).

Figure 1

18 mammalian histone deacetylases (HDACs). It was subdivided into four different categories based on phylogenetic analysis, enzyme activity, and structural domain structure.

Figure 2

Regulatory mechanisms of post-translational modification of HDAC in cardiac hypertrophy. (A). Class I HDAC, when hypertrophy stimulation acts on cardiomyocytes, the expression of HDAC8, HSP70, and CK2α1 is up-regulated. HDAC8 promotes p38 MAPK phosphorylation and increases the expression of cardiac hypertrophic markers, such as ANP and BNP. HSP70 inhibits the expression of antihypertrophic genes by increasing the activity of HDAC2. CK2α1 increases the activity of HDAC2 by promoting the phosphorylation of HDAC2 S394 and promotes cardiac hypertrophy. (B). Class II HDAC, CaMKIIδB induces the dissociation of HDAC from SUV39H1 and MEF2, promotes the phosphorylation of HDAC, reduces the methylation of H3K9, inhibits the transcription of ANP and BNP genes, and thus results lead to the cardiac hypertrophy; CaMK can dissociate HDAC5 from the MEF2 complex, promote the phosphorylation of HDAC5 and the binding of HDAC5 to 14-3-3. (C). Class III HDAC, the reduction of SIRT1 promotes the crotonylation of SERCA2a, which affects the expression of proteins in the PPAR pathway and leads to disorders of energy metabolism; the induction of phenylephrine leads to the reduction of SIRT6 expression and deacetylase activity, which through transcriptional regulation leads to the elevation of Akt expression, which in turn promotes the phosphorylation of p300 and inhibits the degradation of ubiquitin-proteasome. It also leads to the acetylation of p65, a subunit of NF-κB, which has enhanced transcriptional activity and triggers a hypertrophic response.

Figure 3

Regulatory mechanisms of post-translational modification of HDAC in heart failure. (A). Class I HDAC, HDAC3 is highly expressed in the cardiomyocyte hypertrophy model, which causes DNMT1 deacetylation and inhibits ubiquitination mediated proteome degradation, promotes DNMT1 expression, enters the nucleus and methylates SHP-1 promoter region, down-regulates SHP-1 expression, and leads to heart failure; (B). Class II HDAC, SIRT1 attenuated induced NF-κB expression and downregulated miR-155, which in turn inhibited BNDF expression; SIRT3 expression was downregulated, GSK3β acetylation was enhanced, and its phosphorylation was inhibited, which in turn led to the increased expression of Smad3, c-Jun, and β-catenin, and entry into the nucleus to regulate the expression of pro-fibrotic genes.

Figure 4

Regulatory mechanisms of post-translational modification of HDAC in atherosclerosis. (A). Class I HDAC, the upregulation of HDAC1 promotes deacetylation of HIF-1α, which facilitates miR-224-3p-mediated inhibition of FOSL2 and inhibits atherosclerosis; upon stimulation with Am80, CK2α expression is upregulated, leading to its translocation into the nucleus, where it phosphorylates HDAC2 and interacts with Klf5, which is essential for Klf5 deacetylation. Deacetylated Klf5 dissociates from the p21 promoter, thereby increasing p21 expression. (B). Class II HDAC, BA increased intracellular Ca2⁺ levels and activated the phosphorylation of CaMKKβ, CaMKII, and AMPK, leading to increased phosphorylation of HDAC5 and ERK5, which induced eNOS expression through the MEF2C pathway by increasing KLF2 transcriptional activity; (C). Class III HDAC and DNA damage-induced ATM activation result in the downregulation of LARP7, thereby inhibiting SIRT1 activity and enhancing the acetylation of both p53 and p65. Upon stimulation with ox-LDL, DNMT1 undergoes phosphorylation, which suppresses SIRT6 activity, promotes MRTF-A acetylation, and subsequently alleviates the inhibition of MRTF-A on the ICAM-1 promoter. Additionally, SIRT7 mediates the desuccinylation of PRMT5, facilitating the formation of the PRMT5-Mep50 complex, inducing methylation of SREBP1a, and contributing to the progression of atherosclerosis.

Figure 5

Regulatory mechanism of post-translational modification of HDAC in myocardial ischemia/reperfusion (I/R) injury. (A). Class I HDAC, IPostC treatment decreases the binding of DNMT3b and HDAC2 at the promoter region, thereby enhancing the expression of miR-181a-2-3p, promoting DNA hypomethylation and H3K14 hyperacetylation, and ultimately attenuating the effects of I/R injury. (B). Class III HDAC and TAC treatment upregulated the expression of SIRT3, leading to the deacetylation of IDH2, a reduction in mitochondrial ROS production, and improvement in I/R injury. In elderly cardiomyocytes, elevated SIRT6 levels decreased the acetylation of FoxO1, thereby enhancing its transcriptional activity on Atrogin-1 and promoting the degradation of CHMP2B.