ABSTRACT
Despite advances in the treatment of atherosclerotic cardiovascular disease, it remains the leading cause of death in patients with diabetes. Even when risk factors are mitigated, the disease progresses, and thus newer targets need to be identified that directly inhibit the underlying pathobiology of atherosclerosis in diabetes. A single cell sequencing approach was utilised to distinguish the proatherogenic transcriptional profile in aortic cells in diabetes using a streptozotocin induced-diabetic Apoe-/- mouse model. Human carotid endarterectomy specimens from individuals with and without diabetes were also evaluated via immunohistochemical analysis. Further mechanistic studies were performed in human aortic endothelial cells and human THP-1 derived macrophages. We then performed a preclinical study using an AP-1 inhibitor in a diabetic Apoe-/- mouse model. Single cell RNA sequencing analysis identified the AP-1 complex as a novel target in diabetes-associated atherosclerosis. AP-1 levels were elevated in carotid endarterectomy specimens from diabetic when compared to non-diabetic individuals. AP-1 was validated as a mechanosensitive transcription factor via immunofluorescence staining for regional heterogeneity of endothelial cells of the aortic region exposed to turbulent blood flow and by performing microfluidics experiments in HAECs. AP-1 inhibition with T-5224 blunted endothelial cell activation as assessed by a monocyte adhesion assay and expression of genes relevant to endothelial function. Furthermore, AP-1 inhibition attenuated foam cell formation. Critically, treatment with T-5224 attenuated atherosclerosis development in diabetic Apoe-/- mice. This study has identified the AP-1 complex as a novel target, inhibition of which treats the underlying pathobiology of atherosclerosis in diabetes.
ABSTRACT
Cardiovascular diseases (CVD), including coronary heart disease and stroke, comprise the number one cause of mortality worldwide. A major contributor to CVD is atherosclerosis, which is a low-grade inflammatory disease of vasculature that involves a pathological build-up of plaque within the arterial walls. Studies have shown that regulation of gene expression via transcription factors and epigenetic mechanisms play a fundamental role in transcriptomic changes linked to the development of atherosclerosis. Chromatin remodeling is a reversible phenomenon and studies have supported the clinical application of chromatin-modifying agents for the prevention and treatment of CVD. In addition, pre-clinical studies have identified multiple transcription factors as potential therapeutic targets in combating atherosclerotic CVD. Although interaction between transcription factors and epigenetic mechanisms facilitate gene regulation, a limited number of studies appreciate this crosstalk in the context of CVD. Here, we reviewed this gene regulatory mechanism underappreciated in atherosclerosis, which will highlight the mechanisms underlying novel therapeutics targeting epigenetic modifiers and transcription factors in atherosclerosis.
