ABCG1 deficiency promotes endothelial apoptosis by endoplasmic reticulum stress-dependent pathway

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Endothelial Cell Function

Background:

• ATP-binding cassette transporter G1 (ABCG1) plays a crucial role in cellular cholesterol homeostasis.
• Endothelial dysfunction and apoptosis are key events in cardiovascular diseases.
• The precise role of ABCG1 in endothelial apoptosis remains to be fully elucidated.

Purpose of the Study:

• To investigate the involvement of ABCG1 deficiency in endothelial apoptosis.
• To explore the underlying mechanisms connecting ABCG1 deficiency, cholesterol accumulation, and endoplasmic reticulum (ER) stress in endothelial cells.

Main Methods:

• Human umbilical artery endothelial cells were utilized.
• Cells were transfected with ABCG1 siRNA (small interfering RNA) to silence gene expression and/or an ABCG1 expression plasmid.
• Cholesterol efflux, intracellular lipid content, apoptosis markers, and ER stress molecules (GRP78, CHOP) were assessed.
• Experimental manipulation of cellular cholesterol levels using cholesterol-loaded cyclodextrin and cholesterol depletion was performed.

Main Results:

• Silencing ABCG1 significantly reduced cholesterol efflux to HDL and increased intracellular lipid accumulation.
• ABCG1 deficiency promoted endothelial apoptosis and upregulated ER stress markers (GRP78, CHOP).
• Overexpression of ABCG1 reversed these effects, decreasing apoptosis and ER stress.
• Experimental cholesterol loading induced apoptosis and ER stress in ABCG1-deficient cells, while cholesterol depletion suppressed these responses.

Conclusions:

• Reduction of ABCG1 induces endothelial apoptosis.
• This apoptosis appears to be mediated by intracellular free cholesterol accumulation.
• Subsequent endoplasmic reticulum (ER) stress is a key mechanism linking cholesterol imbalance to endothelial cell death.