Histone Deacetylases and Cardiometabolic Diseases

Abstract

Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes and cardiovascular disease. Genetic and environmental factors are linked through epigenetic mechanisms to the pathogenesis of cardiometabolic disease. Post-translational modifications of histone tails, including acetylation and deacetylation, epigenetically alter chromatin structure and dictate cell-specific gene expression patterns. The histone deacetylase (HDAC) family is comprised of 18 members that regulate gene expression by altering the acetylation status of nucleosomal histones and by functioning as nuclear transcriptional co-repressors. HDACs regulate key aspects of metabolism, inflammation, and vascular function pertinent to cardiometabolic disease in a cell- and tissue-specific manner. HDACs also likely play a role in the “metabolic memory” of diabetes, an important clinical aspect of the disease. Understanding the molecular, cellular, and physiological functions of HDACs in cardiometabolic disease is expected to provide insight into disease pathogenesis, risk factor control, and therapeutic development.

Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation

“…Two of the most interesting targets are PPAR isoforms PPARα and PPARγ, known to regulate lipid and glucose homeostasis through their coordinated activities in liver, muscle, and adipose tissue (45). Our findings of increased PPARα and PPARγ in tx-j mice correspond to a study indicating changes in PPARα and PPARγ in WD patients (27). Previous studies have shown PPARα increases with mild liver damage and decreases with moderate or greater liver damage, while PPARγ was increased in WD patients concomitantly with the progression of liver damage.…”

“…Peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) were selected from the TF gene analysis for further examination as they are key regulators of lipid metabolism. PPARα and PPARγ were also shown to be associated with steatosis and the antioxidant response, and exhibited decreased and increased protein levels, respectively, concomitant with liver damage severity in patients with WD (27). During an early stage of disease progression (9 weeks of age), Pparγ transcript levels were significantly higher in tx-j than C3H mice and Pparα transcript levels were reduced, but 8 days of HFD were associated with significantly increased Pparα expression (Figure 6C).…”

Epigenomes in Cardiovascular Disease

“… 57 Sirtuin isoforms have also been shown to exert salubrious effects on fatty acid, amino acid, and glucose metabolism in mouse studies, which have led to clinical trials. 58 A search at clinicaltrials.gov with the keywords cardiovascular disease and epigenetics revealed 29 studies in the active or recently completed phase. These studies range in their employment of epigenetic measurements or interventions.…”

Targeting the epigenome in in-stent restenosis: from mechanisms to therapy

“…Previous studies in animal models have shown that reversible acetylation plays a crucial role in cardiovascular disorders, such as vascular diseases, heart failure, hypertension, arrhythmia, and angiogenesis. 75 HATs are classified into three major families: (1) GCN5-related N -acetyltransferases (GNATs), (2) p300/CREB-binding protein (p300/CBP), and (3) and the MOZ, Ybf2, Sas2, and Tip60 (MYST) family. 76 Histone acetylation increases gene expression by “opening” the chromatin structure.…”