Oxidative modification of HDL by lipid aldehydes impacts HDL function

Abstract

Reduced levels of high-density lipoprotein (HDL) cholesterol correlate with increased risk for atherosclerotic cardiovascular diseases and HDL performs functions including reverse cholesterol transport, inhibition of lipid peroxidation, and suppression of inflammation, that would appear critical for cardioprotection. However, several large clinical trials utilizing pharmacologic interventions that elevated HDL cholesterol levels failed to provide cardioprotection to at-risk individuals. The reasons for these unexpected results have only recently begun to be elucidated. HDL cholesterol levels and HDL function can be significantly discordant, so that elevating HDL cholesterol levels may not necessarily lead to increased functional capacity, particularly under conditions that cause HDL to become oxidatively modified, resulting in HDL dysfunction. Here we review evidence that oxidative modifications of HDL, including by reactive lipid aldehydes generated by lipid peroxidation, reduce HDL functionality and that dicarbonyl scavengers that protect HDL against lipid aldehyde modification are beneficial in pre-clinical models of atherosclerotic cardiovascular disease.

Keywords: Atherosclerosis; HDL; Isolevuglandins; Lipid aldehydes; Malondialdehyde; apoA1.

Figure 1.

Major anti-atherosclerotic functions of HDL. HDL has a critical role in reverse cholesterol transport, as HDL acquires free cholesterol (FC) from macrophages and other cells in peripheral tissues, esterifies FC to cholesterol esters, and then transports cholesterol esters to the liver for excretion by hepatocytes. Antioxidative effects of HDL include inhibiting the oxidation of LDL and the formation of lipid peroxides (LOOH). PON1 plays a major role in HDL’s antioxidative effect both through its catalytic activity and by competing with MPO for binding to apoA1. Other proteins associated with HDL have also been shown to exert antioxidative effects. HDL exerts potent anti-inflammatory effects including suppression of cytokine secretion by endothelial cells and macrophages in response to inflammatory stimuli.

Figure 2.

Effects of oxidative modification on HDL function. Oxidative modifications of HDL include modification of amino acid residues by reactive oxygen species (ROS) formed by MPO, by isocyanate formed non-enzymatically by oxidation of urea, or by various reactive lipid aldehydes formed by lipid peroxidation. These lipid aldehydes include malondialdehyde (MDA), isolevuglandin (IsoLG), acrolein (ACR), 4-oxononenal (ONE), and 4-hydroxynonenal (HNE). The sites of apoA1 amino acid residue modification by each compound is shown as well as other known HDL protein modifications.

Figure 3.

2-aminomethylphenols (2-AMPs) including 2-hydroxybenzylamine (2-HOBA), pentylpyridoxamine (PPM) or pyridoxamine (PM) react with IsoLG or other lipid dicarbonyls to scavenge these dicarbonyls and thus blocking the modification of proteins by these lipid dicarbonyls. The high rate of reactivity of 2-AMPs is the result of their phenolic hydrogen helping to stabilize the initial imine adduct through hydrogen bonding and thereby helping to catalyze pyrrole formation. Inactive analogs of 2-AMP cannot participate in the same reaction and so can be used a control compounds for cellular and in vivo studies.