MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Inflammation Research

Background:

• Atherosclerosis is a chronic inflammatory arterial disease driven by hyperlipidemia and endothelial cell (EC) dysfunction.
• Disturbed laminar flow at specific arterial sites compromises EC function, promoting atherosclerotic lesion development.
• MicroRNAs (miRNAs) play critical roles in regulating cellular processes relevant to cardiovascular health.

Purpose of the Study:

• To investigate the role of endothelial miR-126-5p in maintaining EC proliferation and preventing atherosclerosis.
• To elucidate the molecular mechanism by which miR-126-5p regulates EC function under hyperlipidemic stress.
• To assess the therapeutic potential of miR-126-5p in mitigating atherosclerotic lesion formation.

Main Methods:

• Utilized Mir126(-/-) mice to study the effects of miR-126-5p deficiency on EC proliferation and atherosclerosis.
• Analyzed the expression of miR-126-5p, delta-like 1 homolog (Dlk1), and other relevant markers in ECs.
• Investigated EC recovery after denudation and atherosclerotic lesion formation at predilection and nonpredilection sites.
• Administered miR-126-5p to assess its therapeutic efficacy in a mouse model of atherosclerosis.

Main Results:

• Lack of endothelial miR-126-5p impaired EC proliferation and endothelial recovery after denudation by derepressing Dlk1.
• High miR-126-5p levels conferred a proliferative reserve in ECs at nonpredilection sites, compensating for hyperlipidemia.
• Disturbed flow downregulated miR-126-5p at predilection sites, abrogating EC proliferation and promoting atherosclerosis.
• miR-126-5p administration rescued EC proliferation and limited atherosclerotic lesion formation in mice.

Conclusions:

• Endothelial miR-126-5p is crucial for maintaining EC proliferative capacity and preventing atherosclerosis.
• miR-126-5p suppresses Dlk1, a key inhibitor of EC proliferation, thereby protecting against hyperlipidemia-induced damage.
• Targeting endothelial miR-126-5p represents a promising therapeutic strategy for atherosclerosis.