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

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 (HDL CAD ) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDL CAD 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.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…146 Recent studies linked the loss of endothelial HDL functionality in CAD and ACS patients to the increased content of the lipid peroxidation product malondialdehyde (MDA) in HDL due to reduced PON1 activity. 40 HDL-mediated nitric oxide production in endothelial cells was found impaired in patients with either stable CAD or ACS. 40 This impairment was the result of decreased eNOS-activating phosphorylation at Ser1177 and eNOS-inhibiting phosphorylation at Thr495 as well as increased endothelial superoxide production in response to patient HDL.…”

“…133 However, our lab did not find any reduced binding of HDL from CAD patients with endothelial dysfunction. 40 As discussed before, the very small proportion of apoA-I molecules containing MPO-modified amino acid residues is also unlikely to explain the reduced endothelial functionality of HDL from CAD patients by loss-of-function in SR-BI interaction.…”

“…For example, HDL of patients with CAD or chronic kidney disease (CKD) was found to inhibit rather than stimulate nitric oxide production because it gained the ability to interact with the lectin-like oxidized LDL receptor LOX-1 and the toll-like receptors TLR2 and TLR4, respectively. 40,41 Dysfunctional HDL in cardiovascular disease is not limited to CAD and acute coronary syndrome (ACS). Also in other cardiovascular diseases, such as heart failure, 42 ischaemic cardiomyopathy, 43 heart transplantion, 44,45 as well as in many conditions that are known to increase cardiovascular risk such as diabetes, CKD, acute and chronic inflammatory diseases, or familial hypercholesterolemia, [46][47][48] HDL has been found to lose its atheroprotective characteristics.…”

“…By contrast gain-of-dysfunction, for example the atypical interaction with LOX-1, 40 can explain how quantitatively very minor modifications can lead to endothelial dysfunction.…”

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…As reviewed extensively by März et al, HDL confers protection from damage, necrosis, and the apoptosis of endothelial cells 62. However, HDL from patients with CAD, hypertension, diabetes mellitus, chronic kidney dysfunction, and obesity (independent of its concentration) turns dysfunctional and shows diminished cholesterol efflux capacity and blunted capability of eNOS activation 62, 63…”