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Modification of HDL by reactive aldehydes alters select cardioprotective functions of HDL in macrophages
Rebecca L Schill1, Darcy A Knaack1, Hayley R Powers1
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
Insights
Reactive aldehyde modification of high-density lipoprotein (HDL) impairs its protective functions against cardiovascular disease by affecting macrophage migration and increasing reactive oxygen species. The impact varies depending on the specific aldehyde modification.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Research
Background:
- High-density lipoprotein (HDL)-cholesterol levels are traditionally linked to cardiovascular protection.
- Emerging evidence suggests HDL function, not just cholesterol levels, is a critical determinant of cardiovascular risk.
- Reactive aldehydes like acrolein (Acro), 4-hydroxynonenal, and malondialdehyde (MDA) can modify HDL, potentially compromising its athero-protective properties.
Purpose of the Study:
- To investigate how modification of HDL by reactive aldehydes affects its athero-protective functions in macrophages.
- To determine if aldehyde modification of HDL impairs macrophage migration and influences reactive oxygen species (ROS) generation.
- To explore the signaling pathways and inflammatory responses associated with aldehyde-modified HDL in macrophages.
Main Methods:
- Isolation of primary peritoneal macrophages from C57BL6/J mice.
- Modification of HDL with acrolein (Acro) and malondialdehyde (MDA).
- Assessment of macrophage migration, ROS generation, and inflammatory marker expression following incubation with native and modified HDL.
Main Results:
- Acro- and MDA-modified HDL demonstrated impaired ability to promote macrophage migration compared to native HDL.
- Incubation with MDA-modified HDL increased ROS generation in macrophages.
- Aldehyde modification of HDL did not significantly alter canonical nuclear factor-kappa B (NF-κB) signaling or inflammatory marker expression in macrophages.
- The functional changes in HDL were dependent on the specific type of aldehyde modification.
Conclusions:
- Modification of HDL by reactive aldehydes can impair specific athero-protective functions, including macrophage migration and ROS modulation.
- These functional impairments may not be mediated by canonical NF-κB inflammatory pathways.
- The extent of HDL dysfunction is specific to the type of aldehyde modification, highlighting the complexity of HDL's role in cardiovascular health.
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.
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