Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Area of Science:

• Cardiovascular Biology
• Endothelial Function
• Lipid Metabolism

Background:

• High-density lipoprotein (HDL) is investigated for coronary artery disease (CAD) treatment due to its presumed atheroprotective endothelial effects.
• However, HDL's impact on endothelial function in CAD patients, specifically its effects on endothelial nitric oxide synthase (eNOS) pathways, remains unclear.

Purpose of the Study:

• To investigate the endothelial effects of HDL from patients with CAD.
• To elucidate the mechanisms by which CAD-associated HDL may impair endothelial function and nitric oxide (NO) production.

Main Methods:

• Comparison of HDL from healthy subjects versus HDL from CAD patients (HDLCAD) regarding endothelial anti-inflammatory and repair effects.
• Assessment of HDLCAD's impact on endothelial NO production, eNOS activation, and related signaling pathways.
• Investigation of the role of lectin-like oxidized LDL receptor 1 (LOX-1) and protein kinase C beta-II (PKCβII) activation.
• Analysis of HDL-associated paraoxonase 1 (PON1) activity and malondialdehyde levels.

Main Results:

• HDL from CAD patients (HDLCAD) failed to provide anti-inflammatory effects or stimulate endothelial repair, unlike HDL from healthy individuals.
• HDLCAD activated endothelial LOX-1, leading to PKCβII activation, which inhibited eNOS-activating pathways and NO production.
• Reduced HDL-associated PON1 activity was identified as a key factor contributing to these detrimental endothelial effects of HDLCAD, linked to increased malondialdehyde formation.

Conclusions:

• In CAD patients, HDL acquires properties that activate endothelial LOX-1 and PKCβII due to diminished PON1 activity.
• This activation pathway inhibits eNOS signaling, resulting in the loss of HDL's beneficial anti-inflammatory and endothelial repair-stimulating effects.
• These findings reveal a novel mechanism for endothelial dysfunction in CAD mediated by altered HDL properties.