Understanding Myeloperoxidase-Induced Damage to HDL Structure and Function in the Vessel Wall: Implications for HDL-Based Therapies

Abstract

Atherosclerosis is a disease of increased oxidative stress characterized by protein and lipid modifications in the vessel wall. One important oxidative pathway involves reactive intermediates generated by myeloperoxidase (MPO), an enzyme present mainly in neutrophils and monocytes. Tandem MS analysis identified MPO as a component of lesion derived high-density lipoprotein (HDL), showing that the two interact in the arterial wall. MPO modifies apolipoprotein A1 (apoA-I), paraoxonase 1 and certain HDL-associated phospholipids in human atheroma. HDL isolated from atherosclerotic plaques depicts extensive MPO mediated posttranslational modifications, including oxidation of tryptophan, tyrosine and methionine residues, and carbamylation of lysine residues. In addition, HDL associated plasmalogens are targeted by MPO, generating 2-chlorohexadecanal, a pro-inflammatory and endothelial barrier disrupting lipid that suppresses endothelial nitric oxide formation. Lesion derived HDL is predominantly lipid-depleted and cross-linked and exhibits a nearly 90% reduction in lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity. Here we provide a current update of the pathophysiological consequences of MPO-induced changes in the structure and function of HDL and discuss possible therapeutic implications and options. Preclinical studies with a fully functional apoA-I variant with pronounced resistance to oxidative inactivation by MPO-generated oxidants are currently ongoing. Understanding the relationships between pathophysiological processes that affect the molecular composition and function of HDL and associated diseases is central to the future use of HDL in diagnostics, therapy, and ultimately disease management.

Keywords: HDL; cholesterol efflux capacity; myeloperoxidase; paraoxonase; post-translational modification.

Figure 1

Endothelium-protective activities of HDL. HDL particles exert several protective effects on the endothelium, including reduction of reactive oxygen species (ROS), the improvement of endothelial barrier function, and promotion of vascular relaxation by increasing endothelial nitric oxide synthase (eNOS) activity. Moreover, HDL inhibits endothelial cell apoptosis, suppresses the expression of endothelial adhesion molecules, and stimulates endothelial cell repair. In addition, HDL promotes reverse cholesterol transport, by uptake of cholesterol from macrophages and other peripheral cells. Transendothelial transport of HDL is mediated by scavenger receptor B1 (SR-BI), ATP-binding cassette G1 (ABCG1), and endothelial lipase (EL).

Figure 2

Effect of MPO-induced oxidative modifications on HDL function. In the atherosclerotic vessel wall, HDL/apoA-I is a target for MPO-catalyzed oxidation. Specifically, the MPO products hypochlorus acid (HOCl⁻), cyanate (OCN⁻) and peroxynitrite (ONOO⁻) lead to chlorination, carbamylation, nitration and the formation of the plasmalogen oxidation product 2-Chlorohexadecanal (2-ClHDA). Oxidative modifications of HDL by MPO results in loss of HDL’s ability to activate endothelial nitric oxide synthase (eNOS). Moreover, MPO modified HDL compromises endothelial barrier function and upregulates endothelial adhesion molecule expression. Further, MPO-catalyzed oxidation of HDL impairs cholesterol efflux capacity via ABCA1, whereas affinity for SR-BI increases. MPO also targets PON1 and leads to decreased activity. Oxidative modifications of apoA-I result in a profoundly decreased activity of LCAT. ApoA-I, apolipoprotein A1; MPO, myeloperoxidase; ABCA1, ATP-binding cassette transporter A1.