Epigenetic Regulation of ATP-Binding Cassette Protein A1 (ABCA1) Gene Expression: A New Era to Alleviate Atherosclerotic Cardiovascular Disease.

Mohamed Zaiou,Ahmed Bakillah

doi:10.3390/diseases6020034

Abstract

The most important function of high density lipoprotein (HDL) is its ability to remove cholesterol from cells and tissues involved in the early stages of atherosclerosis back to the liver for excretion. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of cholesterol efflux to HDL in macrophage foam cells. Thus, promoting the process of reverse cholesterol transport (RCT) by upregulating mainly ABCA1 remains one of the potential targets for the development of new therapeutic agents against atherosclerosis. Growing evidence suggests that posttranscriptional regulation of HDL biogenesis as well as modulation of ABCA1 expression are under the control of several genetic and epigenetic factors such as transcription factor (TFs), microRNAs (miRNAs) and RNA-binding proteins (RBPs).These factors may act either individually or in combination to orchestrate ABCA1 expression. Complementary to our recent work, we propose an exploratory model for the potential molecular mechanism(s) underlying epigenetic signature of ABCA1 gene regulation. Such a model may hopefully provide the basic framework for understanding the epigenetic regulation of RCT and contribute to the development of novel therapeutic strategies to alleviate the burden of cardiovascular diseases (CVD).

Highlights

Based on the general consensus that high density lipoprotein (HDL) protects against atherosclerotic cardiovascular diseases (CVD), several attempts have been made to design drugs that raise HDL cholesterol (HDL-C) levels or enhance its cardioprotective function
We propose a hypothetical model for the potential dynamic interplay between different genetic and epigenetic regulators that may serve to regulate ABCA1 gene enabling the cell to respond to different environment changes (Figure 1)
Emerging research suggests that deregulated miRNAs can impact reverse cholesterol transport (RCT) gene networks, mainly

Summary

Introduction

Based on the general consensus that HDL protects against atherosclerotic CVD, several attempts have been made to design drugs that raise HDL cholesterol (HDL-C) levels or enhance its cardioprotective function. The dysregulation of miRNAs has been associated with the disruption of multiple gene networks leading to metabolic disorders including diabetes, obesity, metabolic syndrome and atherosclerosis [2,3]. This clearly indicates that beyond the existing therapies, advance in epigenetics mechanisms could offer additional opportunities to develop novel treatment strategies for atherosclerosis. In this regard, attempts have been made to develop Apabetalone (RVX-208) as the first epigenetic approach to treat CVD. RCT genes network, mainly ABCA1 gene that is involved in the initiation of this process, may bring insights into novel therapeutic approaches for treating atherosclerotic vascular disease

Discussion

Schematic

Conclusions and Perspectives