High-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Biochemistry

Background:

• High-density lipoprotein (HDL) plays a dual role in angiogenesis, with normal HDL (nHDL) promoting it and HDL from coronary artery disease patients (dHDL) impairing it.
• Autophagy is crucial for angiogenesis, and HDL's regulation of autophagy is a key area of investigation.
• The specific mechanisms by which nHDL and dHDL influence autophagy and subsequently affect angiogenesis remain unclear.

Purpose of the Study:

• To investigate whether nHDL and dHDL regulate angiogenesis by modulating autophagy.
• To elucidate the role of microRNA (miRNA) and autophagy-related protein 5 (ATG5) in HDL-mediated regulation of endothelial cell function.
• To explore the therapeutic potential of targeting HDL-mediated autophagy for angiogenesis dysfunction.

Main Methods:

• Endothelial cells (ECs) were treated with nHDL and dHDL, with or without autophagy inhibitors, to assess autophagy, eNOS expression, miRNA profiles, nitric oxide (NO) production, superoxide anion (O2•−) generation, and cell migration/tube formation.
• Investigated the direct targeting relationship between miR-181a-5p and ATG5 using molecular biology techniques.
• Utilized hypercholesterolemic low-density lipoprotein receptor null (LDLr-/-) mice and C57BL/6 mice to evaluate ATG5 expression and angiogenesis in vivo.

Main Results:

• nHDL suppressed miR-181a-5p, enhancing autophagy, eNOS expression, NO production, and EC migration/tube formation, while reducing O2•− generation.
• dHDL exhibited opposite effects, increasing miR-181a-5p, inhibiting autophagy and eNOS, decreasing NO production, and impairing EC migration/tube formation.
• ATG5 was identified as a direct target of miR-181a-5p; its modulation mimicked or reversed the effects of nHDL and dHDL on angiogenesis and autophagy.

Conclusions:

• nHDL promotes angiogenesis by suppressing miR-181a-5p, thereby stimulating autophagy and eNOS expression, leading to increased NO production.
• dHDL inhibits angiogenesis by increasing miR-181a-5p, which suppresses autophagy and eNOS, reducing NO and increasing oxidative stress.
• These findings reveal a novel mechanism of HDL-mediated angiogenesis regulation via autophagy and identify ATG5 and miR-181a-5p as potential therapeutic targets.