Modification of HDL by reactive aldehydes alters select cardioprotective functions of HDL in macrophages

Abstract

While increased levels of high‐density lipoprotein (HDL)‐cholesterol correlate with protection against cardiovascular disease, recent findings demonstrate that HDL function, rather than HDL‐cholesterol levels, may be a better indicator of cardiovascular risk. One mechanism by which HDL function can be compromised is through modification by reactive aldehydes such as acrolein (Acro), 4‐hydroxynonenal, and malondialdehyde (MDA). In this study, we tested the hypothesis that modification of HDL with reactive aldehydes would impair HDL’s athero‐protective functions in macrophages. Compared to native HDL, Acro‐ and MDA‐modified HDL have impaired abilities to promote migration of primary peritoneal macrophages isolated from C57BL6/J mice. Incubation of macrophages with MDA‐HDL also led to an increased ability to generate reactive oxygen species. Our studies revealed that the changes in HDL function following aldehyde modification are likely not through activation of canonical nuclear factor‐kappa B signaling pathways. Consistent with this finding, treatment of either noncholesterol‐loaded macrophages or foam cells with modified forms of HDL does not lead to significant changes in expression levels of inflammatory markers. Importantly, our data also demonstrate that changes in HDL function are dependent on the type of modification present on the HDL particle. Our findings suggest that modification of HDL with reactive aldehydes can impair some, but not all, of HDL’s athero‐protective functions in macrophages.

Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein

“…It has been reported that the cholesterol efflux function of HDL decreases when it is modified by reactive aldehydes [65,68]. In addition, HDL obtained from patients with acute coronary syndrome had lower PON1 activity, more oxidative modifications on apoA1, and more MCP-1 gene expression in endothelial cells than HDL from normal subjects [102].…”

“…Oxidation of Met112 or chlorination of Tyr192 of apoA1 by MPO-dependent modifications reduced its cholesterol efflux capacity [60,63]. In addition, oxHDL increased LOX-1 expression in endothelial cells [67] and decreased migration of macrophages [68], which are thought to be regulated through NF-kB dependent pathways.…”

Editorial: The Roles of Lipids in Immunometabolism: The Crosstalk Between Lipid Metabolisms and Inflammation

“…Alternatively, since HDL reduce peripheral cell cholesterol levels by mediating cholesterol efflux or reverse cholesterol transport, do HDL impose beneficial effects on immune system indirectly through alleviating the cellular lipid burden? In addition, similar to LDL, HDL can be chemically modified, which appear to impair their physiological functions ( 22 , 23 ). It would be highly interesting to further explore the impact of the modified HDL in vivo and how they alter systemic inflammation in metabolic diseases.…”

Association of anti-oxidative capacity of HDL with subclinical atherosclerosis in subjects with and without non-alcoholic fatty liver disease

“…MDA generates lysine adducts on apoA-1 and blocks the cholesterol efflux function of HDL [ 20 ]. Incubation of macrophages with MDA modified HDL also led to an increased ability to generate ROS [ 21 ]. The antioxidant enzymes including superoxide dismutase and PON1 diminish ROS and lipid peroxidation.…”