High-density lipoprotein regulates angiogenesis by long non-coding RNA HDRACA

Area of Science:

• Molecular Biology
• Cardiovascular Research
• RNA Biology

Background:

• Normal high-density lipoprotein (nHDL) promotes angiogenesis, but dysfunctional HDL (dHDL) from coronary artery disease patients loses this ability.
• The mechanisms underlying HDL's regulation of angiogenesis and the role of dysfunctional HDL remain incompletely understood.

Purpose of the Study:

• To identify novel molecular regulators involved in HDL-mediated angiogenesis.
• To elucidate the role of a long non-coding RNA, HDRACA, in the differential effects of nHDL and dHDL on angiogenesis.

Main Methods:

• Investigated the interaction between HDL, endothelial cells, and HDRACA expression.
• Utilized molecular biology techniques including RNA sequencing, protein ubiquitination assays, and mRNA-protein binding analysis.
• Employed a hindlimb ischemia mouse model to assess the in vivo function of HDRACA in angiogenesis.

Main Results:

• nHDL downregulates HDRACA expression in endothelial cells via S1P receptor 1 and WW domain-containing E3 ubiquitin protein ligase 2, targeting Kruppel-like factor 5.
• dHDL, with lower sphingosine 1-phosphate (S1P) levels, was less effective in downregulating HDRACA.
• HDRACA inhibits angiogenesis by interacting with Ras-interacting protein 1 (RAIN), disrupting RAIN-vigilin interaction, and consequently reducing proliferating cell nuclear antigen (PCNA) mRNA binding to vigilin.
• Overexpression of HDRACA in a mouse model impaired angiogenesis recovery.

Conclusions:

• HDRACA is a key mediator in HDL's regulation of angiogenesis.
• nHDL induces angiogenesis by suppressing HDRACA expression, while dHDL's diminished capacity to do so explains its angiogenic dysfunction.
• HDRACA represents a potential therapeutic target for cardiovascular diseases characterized by impaired angiogenesis.