The Therapeutic Potential of Epigenome-Modifying Drugs in Cardiometabolic Disease

Abstract

Cardiometabolic disorders, including cardiovascular disease, obesity and type 2 diabetes, are an extreme burden on the health of individuals and societies worldwide. The combination of genetic susceptibility, environmental and lifestyle factors drives disease development. Therefore, understanding the exact molecular changes occurring in their pathogenesis brings not only insights into mechanism but also potential novel therapeutic angles. Epigenetic changes—the mitotically heritable chemical marks or packaging of DNA that influence gene expression without changing the genetic code itself—have been identified as highly compelling targets. Therapeutic success modulating the epigenome has initially come in cancer but is now expanding into non-malignant diseases. Here, we discuss the different epigenetic mechanisms implicated in cardiometabolic disease and the advancing science of epigenetic therapeutics for these disorders. Disruption of epigenetic networks can be causative in cardiometabolic diseases, including, for example, endothelial dysfunction and vascular ageing. Epigenomic changes may also influence or indicate known risk factors, including hypertension, inflammation and dyslipidemia. The dynamic plasticity that characterises the epigenome lends itself to therapeutic manipulation with many epigenetic drugs now under clinical trials and others have already been approved for medical use. Major epigenetic inhibitor classes include the following: DNA methyltransferase inhibitors (DNMTi); histone deacetylase inhibitors (HDACi); isocitrate dehydrogenase inhibitors (IDHi); bromodomain and the extra-terminal motif protein inhibitors (BETi) and EZH2 inhibitors (EZH2i) with natural and synthetic examples of these possessing potential cardiometabolic effects. For example, there is accumulating evidence for the BETi Apabetalone to reduce vascular inflammation, thereby decreasing cardiovascular events, and the HDACi sodium butyrate to suppress experimentally inflammatory cytokines in atherosclerosis. Despite challenges in the development and application of epigenetic drugs, the achievements in oncology and increasing experimental evidence indicate the clinical utility of targeting the readers, writers and erasers of the epigenome. Therefore, precise modification of epigenetic information is likely to be a key player in the future of personalised therapeutic approaches in individuals with cardiometabolic disorders.