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Published on: March 24, 2017
MicroRNA-22 inhibition promotes the development of atherosclerosis via targeting interferon regulator factor 5
Zhenhua Wu1, Jie Geng2, Yunpeng Bai3
1Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300222, China; Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, 300073, China.
Abstract:
Atherosclerosis is generally accepted as a chronic inflammatory disease and is the most important pathological process underlying the cardiovascular diseases. MiR-22 exerts an important role in tumorgenesis, obesity and NAFLD development, as well as cardiovascular diseases. However, a certain role of miR-22 in the pathogenesis of atherosclerosis remains undetermined. Here, we showed that miR-22 exhibited a negative association with the deteriorated atherosclerotic plaque and showed significant downregulated expression in macrophages. Next, treatment of ApoE deficiency (ApoE-/-) mice with miR-22 inhibitors which were then subjected to high fat diet (HFD) for 12 weeks were performed to investigate the function of miR-22 on atherogenesis. The results exhibited that miR-22 inhibition dramatically promoted atherosclerotic plaques but attenuated plaque stabilization which were accompanied by decreased smooth muscle cell and collagen content, but increased macrophage infiltration and lipid accumulation. More importantly, the in vivo and in vitro experiments suggested that miR-22 inhibition accelerated inflammatory response and foam cell formation. Mechanistically, we demonstrated interferon regulator factor 5 (IRF5) was an important target of miR-22 and it was required for the regulation of inflammation mediated by miR-22 inhibition. Collectively, these evidences revealed that miR-22 inhibition promoted the atherosclerosis progression through activation of IRF5.
Insights
MicroRNA-22 (miR-22) downregulation promotes atherosclerosis progression by increasing inflammation and plaque instability. Inhibiting miR-22 activates IRF5, exacerbating cardiovascular disease development.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Inflammation Research
Background:
- Atherosclerosis is a chronic inflammatory disease central to cardiovascular diseases.
- MicroRNA-22 (miR-22) has known roles in various conditions, but its specific function in atherosclerosis pathogenesis is unclear.
- Previous studies indicate miR-22 expression is linked to cardiovascular health.
Purpose of the Study:
- To elucidate the role of miR-22 in the development and progression of atherosclerosis.
- To investigate the molecular mechanisms by which miR-22 influences atherosclerotic plaque stability and inflammation.
- To determine if miR-22 inhibition impacts atherogenesis in a mouse model.
Main Methods:
- Analysis of miR-22 expression in atherosclerotic plaques and macrophages.
- Utilizing ApoE-deficient mice subjected to a high-fat diet and treated with miR-22 inhibitors.
- In vivo and in vitro experiments to assess inflammatory response, foam cell formation, and plaque characteristics.
- Investigating the regulatory relationship between miR-22 and Interferon Regulator Factor 5 (IRF5).
Main Results:
- miR-22 expression was negatively associated with atherosclerotic plaque severity and downregulated in macrophages.
- Inhibition of miR-22 significantly promoted atherosclerotic plaque formation and instability in ApoE-/- mice.
- miR-22 inhibition led to decreased smooth muscle cell and collagen content, increased macrophage infiltration and lipid accumulation.
- miR-22 inhibition accelerated inflammatory response and foam cell formation, mediated by the activation of IRF5.
Conclusions:
- miR-22 plays a protective role in atherosclerosis, with its downregulation promoting disease progression.
- Inhibition of miR-22 exacerbates atherosclerosis by increasing inflammation and destabilizing plaques.
- The miR-22/IRF5 axis is a critical pathway regulating inflammatory responses in atherosclerosis.
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