Acylations in cardiovascular biology and diseases, what's beyond acetylation

Abstract

Metabolism regulates cardiovascular biology through multiple mechanisms, including epigenetic modifications. Over the past two decades, experimental and preclinical studies have highlighted the critical roles of histone modifications in cardiovascular development, homeostasis, and diseases. The widely studied histone acetylation is critical in cardiovascular biology and diseases, and inhibitors of histone deacetylases show therapeutic values. In addition to lysine acetylation, a series of novel non-acetyl lysine acylations have recently been recognized. These non-acetyl lysine acylations have been demonstrated to have physiological and pathological functions, and recent studies have analyzed the roles of these non-acetyl lysine acylations in cardiovascular biology. Herein, we review the current advances in the understanding of non-acetyl lysine acylations in cardiovascular biology and discuss open questions and translational perspectives. These new pieces of evidence provide a more extensive insight into the epigenetic mechanisms underlying cardiovascular biology and help assess the feasibility of targeting acylations to treat cardiovascular diseases.

Keywords: Cardiovascular biology; Cardiovascular disease; Epigenetics; Metabolism; Metabolite; Non-acetyl acylation.

Fig. 1

Origin of acyl-CoAs and functions of lysine acylations. Diet digestion, fermentation of dietary fibers by the gut microbes, and intracellular energy metabolism (fatty acid oxidation and amino acid catabolism) can generate various metabolites, such as LCFAs, SCFAs, amino acids, glucose, and ketones, which can enter cells and generate acyl-CoAs. Intracellular acyl-CoAs not only serve as substrates to support ATP generation, but also act as donors for PTMs of histones and non-histone proteins, which are critical mechanisms controlling the transcriptome, proteome, and metabolome. ACSS2 can convert SCFAs into cognate short-chain acyl-CoAs, which provide direct donors for short-chain lysine acylations of histone or non-histone proteins. PTMs can regulate transcription, signal transduction, and protein function, and these acylations are closely associated with the development of CVDs and CVD-related risk factors. LCFA, long-chain fatty acid; SCFA, short-chain fatty acid; PTM, post-translational modification; DDR, DNA damage repair; ACSS2, Acyl-CoA Synthetase Short Chain Family Member 2.

Fig. 2

Histone propionylation and malonylation regulate cardiovascular homeostasis. Metabolic syndromes, such as diabetes, induce an increase in circulating BCAA, which contributes to increased propionyl-CoA via unknown mechanisms. Propionyl-CoA promotes propionylation and activation of TPM3, thereby increasing platelet activation and the risk of thrombosis. Histone propionylation is mediated by the BRPF1-KAT6 complex, the deficiency of which induces a dilated ascending aorta. In the cytoplasm, malonylation of mTOR regulates its role in angiogenesis, while malonylation of GAPDH modulates its role as an RNA-binding protein in inflammation regulation. BCAA, branched-chain amino acids; TPM3, tropomyosin 3; BRPF1, bromodomain and PHD finger-containing protein 1; KAT6, lysine acetyltransferase 6; mTOR, mammalian target of rapamycin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; TNFa, tumor necrosis factor-alpha.

Fig. 3

Lactylation regulates vascular function and inflammation. Lactate from glycolysis and excellular transportation leads to the increase of lactyl-CoA via an unknown mechanism. Lactyl-CoA contributes to lactylation of histone and non-histone proteins in macrophages, reprogramming paracrine factors (FGF2), exosomes (HMGB1), and transcriptome (M2-like gene signature) of macrophages to regulate vascular function (angiogenesis, permeability) and chronic inflammation (M2 macrophages), which may contribute to cardiovascular injury and regeneration. GLUT, glucose transporter; MCT, monocarboxylate transporter; FGF2, fibroblast growth factor 2; YY1, Yin Yang 1; HMGB1, High-mobility group box 1.

Fig. 4

Histone crotonylation contributes to cardiac remodeling and heart failure. Aging and other stress such as angiotensin II (Ang II) decrease the expression of mitochondrial ECHS1, which is a short-chain enoyl-CoA hydratase participating in the catabolism of short-chain fatty acids. The deficiency of ECHS1 in cardiomyocytes increases the level of crotonyl-CoA, which promotes histone crotonylation and transcription of genes involved in cardiomyocyte hypertrophy. In fibroblasts, ECHS1 deficiency promotes the nucleus translocation of P300, leading to hyper-acetylation of histone and activation of fibroblast. ECHS1 deficiency induces cardiomyocyte hypertrophy and fibroblast fibrosis contributes to cardiac remodeling and failure. ECHS1, enoyl-CoA hydratase, short chain 1; Nppb, B-type natriuretic peptide.

Fig. 5

Succinylation and glutarylation in cardiovascular diseases. Succinylation and glutarylation were regulated by mitochondrial sirtuins. In animals, the deficiency of mitochondrial enzyme SIRT5 causes hyper-succinylation/glutarylation of mitochondrial metabolic enzymes (e.g., SDH, IDH2, G6PD) and antioxidants, leading to metabolic dysfunction and ROS accumulation in cardiomyocytes and vascular cells, subsequently resulting in the development of cardiovascular (CVDs) and cerebrovascular diseases (CBVDs). MCD, malonyl-CoA-decarboxylase; SDH, succinate dehydrogenase; IDH2, isocitrate dehydrogenase 2; G6PD, glucose-6-phosphate dehydrogenase.