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The Role of Activator Protein-1 Complex in Diabetes-Associated Atherosclerosis: Insights From Single-Cell RNA
Abdul Waheed Khan1, Misbah Aziz1, Karly C Sourris1
1Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
Abstract:
Despite advances in treatment, atherosclerotic cardiovascular disease 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 used 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 (HAECs) and human THP-1-derived macrophages. We then performed a preclinical study using an activator protein-1 (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 individuals with diabetes compared with those without diabetes. 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, the inhibition of which treats the underlying pathobiology of atherosclerosis in diabetes.
Insights
Researchers identified the activator protein-1 (AP-1) complex as a novel target for treating atherosclerosis in diabetes. Inhibiting AP-1 reduced disease progression and key cellular processes involved in this condition.
Area of Science:
- Cardiovascular Biology
- Diabetes Research
- Molecular Medicine
Background:
- Atherosclerotic cardiovascular disease is the primary cause of death in diabetic patients.
- Existing treatments are insufficient, necessitating new therapeutic targets for diabetes-associated atherosclerosis.
- Understanding the specific molecular pathways driving atherosclerosis in diabetes is crucial.
Purpose of the Study:
- To identify novel molecular targets that inhibit the pathobiology of atherosclerosis in diabetes.
- To investigate the role of the activator protein-1 (AP-1) complex in diabetes-associated atherosclerosis.
- To evaluate the therapeutic potential of AP-1 inhibition in preclinical models.
Main Methods:
- Single-cell RNA sequencing in a diabetic Apoe-/- mouse model to identify proatherogenic transcriptional profiles.
- Immunohistochemical analysis of human carotid endarterectomy specimens.
- Mechanistic studies in human aortic endothelial cells and macrophages.
- Preclinical evaluation of an AP-1 inhibitor (T-5224) in diabetic mice.
Main Results:
- Single-cell sequencing identified the AP-1 complex as a novel target in diabetes-associated atherosclerosis.
- AP-1 levels were elevated in human diabetic carotid endarterectomy specimens.
- AP-1 inhibition with T-5224 reduced endothelial cell activation, monocyte adhesion, and foam cell formation.
- T-5224 treatment attenuated atherosclerosis development in diabetic Apoe-/- mice.
Conclusions:
- The AP-1 complex is a key mediator of diabetes-associated atherosclerosis.
- Inhibition of AP-1 represents a promising therapeutic strategy for treating atherosclerosis in diabetic patients.
- Targeting AP-1 addresses the underlying pathobiology of this complex disease.
