MicroRNAs and the response to injury in atherosclerosis

 

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Summary

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 hyperlipid -aemia perturbs this delicate balance of en-dothelial 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.

Zusammenfassung

Endothelzellen werden an der Verzweigung von Arterien physiologischerweise durch gestörte Blutflussverhältnisse chronisch geschä-digt, wodurch eine vaskuläre Wundheilungsreaktion initiiert wird. Eine zusätzliche Schädigung durch Hyperlipidämie stört das emp-findliche Gleichgewicht aus endothelialer Schädigung und Regeneration. In der Folge kommt es zu einer progredienten Akkumulation modifizierter Lipoproteine, die zum Zell-tod von Makrophagen führt. Verschiedene microRNAs, wie miR-92a und miR-712, welche die endotheliale Proliferation und Inflammation regulieren, werden durch gestörte Blutflussverhältnisse hochreguliert und verstärken die Atherosklerose. Ferner beeinträchtigt eine verminderte Expression der miR-126–5p die regenerative Kapazität von Endothelzellen mit der Folge einer unzureichenden endothelialen Regeneration unter hyperlipidämischem Stress. In Makrophagen induziert die miR-342–5p die Expression der miR-155 während der Progression der Atherosklerose. Die Hemmung der BCL6-Expressi-on durch miR-155 verstärkt die Expression inflammatorischer Gene und vermindert die Efferozytose, wodurch die Bildung eines nekrotischen Kerns in atherosklerotischen Plaques gefördert wird. Die Entschlüsselung der komplexen zell- und kontextspezifischen Effekte von miRNAs während der vaskulären Wundheilung ist für die Entwicklung miRNAbasierter Therapien der Atherosklerose elementar.

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