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Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
Christian Besler1, Kathrin Heinrich, Lucia Rohrer
1Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland.
Insights
High-density lipoprotein (HDL) from coronary artery disease (CAD) patients loses its protective endothelial effects. This occurs because HDL activates lectin-like oxidized LDL receptor 1 (LOX-1), inhibiting nitric oxide production crucial for vascular health.
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.
Abstract:
Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.
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