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Published on: August 25, 2020
MicroRNAs and the response to injury in atherosclerosis
1Andreas Schober, MD, Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstr. 9, 80336 Munich, Germany, Tel. +49/(0)89/44 00 54-530; Fax -740,
Abstract:
Endothelial cells (ECs) at arterial branching points are physiologically subjected to chronic damage by disturbed blood flow, which triggers a vascular wound healing response. Additional damage by hyperlipidaemia perturbs this delicate balance of endothelial injury and regeneration, and the progressive accumulation of noxious modified lipoproteins leads to macrophage death. Several miRNAs such as miR-92a and miR-712, which modulate EC proliferation and inflammation, are up-regulated by disturbed flow in ECs, and contribute to atherosclerosis. In addition, reduced endothelial levels of miR-126-5p limit the regenerative capacity of ECs, which becomes apparent by insufficient endothelial repair under hyperlipidemic stress. In macrophages, miR-342-5p induces the expression of miR-155 during the progression of atherosclerosis, which promotes inflammatory gene expression and inhibits efferocytosis by targeting Bcl6, thus contributing to necrotic core formation. Deciphering the complex cell- and context-specific effects of miRNAs during vascular wound healing appears essential for the development of miRNA-based therapies of atherosclerosis.
Insights
MicroRNAs (miRNAs) play a crucial role in vascular wound healing and atherosclerosis. Understanding their specific roles in endothelial cells and macrophages is key to developing new miRNA-based therapies for this disease.
Area of Science:
- Vascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Endothelial cells (ECs) at arterial branches face chronic damage from disturbed blood flow, initiating a wound healing response.
- Hyperlipidemia exacerbates endothelial injury and regeneration imbalance, leading to macrophage death and modified lipoprotein accumulation.
- MicroRNAs (miRNAs) are increasingly recognized as critical regulators in vascular homeostasis and disease pathogenesis.
Purpose of the Study:
- To elucidate the cell- and context-specific roles of miRNAs in endothelial cells and macrophages during vascular wound healing.
- To investigate how dysregulated miRNAs contribute to the progression of atherosclerosis under conditions of disturbed blood flow and hyperlipidemia.
- To identify potential miRNA targets for therapeutic interventions against atherosclerosis.
Main Methods:
- Analysis of miRNA expression profiles in endothelial cells subjected to disturbed blood flow.
- Investigation of miRNA involvement in macrophage responses, including inflammation and efferocytosis.
- Assessment of the impact of specific miRNAs (e.g., miR-92a, miR-712, miR-126-5p, miR-342-5p) on endothelial repair and atherosclerotic lesion development.
Main Results:
- Disturbed blood flow up-regulates pro-atherogenic miRNAs (miR-92a, miR-712) in ECs, promoting inflammation and proliferation.
- Reduced miR-126-5p levels in ECs impair regenerative capacity, hindering repair under hyperlipidemic stress.
- In macrophages, miR-342-5p induces miR-155, promoting inflammation and inhibiting efferocytosis by targeting Bcl6, thus contributing to necrotic core formation.
Conclusions:
- Specific miRNAs exhibit distinct, context-dependent functions in endothelial cells and macrophages during vascular wound healing and atherosclerosis.
- Dysregulation of miRNAs like miR-92a, miR-712, miR-126-5p, and miR-342-5p significantly contributes to atherosclerotic pathology.
- Targeting these miRNAs holds promise for developing novel therapeutic strategies for atherosclerosis.
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