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Updated: Sep 4, 2025
Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
Using adenovirus-mediated gene transfer to study the effect of myeloperoxidase on plasma lipid levels, HDL structure
Katerina Dalakoura-Karagkouni1, Ioanna Tiniakou1, Vassilis I Zannis2
1University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, 71003, Crete, Greece.
Abstract:
Apolipoprotein A-I (apoA-I), the main protein component of High-Density Lipoprotein (HDL), is modified in plasma and the arterial wall by various enzymes. Myeloperoxidase (MPO), a leukocyte-derived peroxidase, is highly expressed during inflammation and associates with HDL reducing its functionality and contributing to atherosclerosis. In the present study we sought to explore further the effect of MPO on HDL structure and functionality in vivo using adenovirus-mediated gene transfer of human MPO combined with human apoA-I forms containing substitutions at MPO-sensitive sites or wild type apoA-I. We found that overexpression of MPO in mice significantly increased plasma apoA-I and HDL levels without affecting the expression of genes involved in HDL biogenesis or catabolism in the liver. Overexpression of MPO in the liver reduced the expression of pro-inflammatory genes and increased or did not affect the expression of anti-inflammatory genes suggesting that MPO had no toxic effects in this organ. In the plasma of mice overexpressing MPO, no significant alterations in HDL size or electrophoretic mobility was observed with the exception of mice expressing apoA-I (M148A) which showed enriched pre-β relative to α HDL particles, suggesting that the apoA-I (M148A) mutation may interfere with HDL remodelling. Overexpression of MPO was associated with reduced anti-oxidant capacity of HDL particles in all mice. Interestingly, HDL particles bearing apoA-I (Y192A) showed enhanced ABCA1-dependent cholesterol efflux from macrophages which was not affected by MPO and these mice had reduced levels of LDL-c. These findings provide new insights on the role of specific amino acid residues of apoA-I in HDL structure and function following modification by MPO. This knowledge may facilitate the development of novel therapies based on improved HDL forms for patients with chronic diseases that are characterized by dysfunctional HDL.
Insights
Myeloperoxidase (MPO) increases High-Density Lipoprotein (HDL) levels but reduces its antioxidant capacity. Specific Apolipoprotein A-I (apoA-I) mutations impact HDL remodeling and cholesterol efflux, offering potential therapeutic targets for cardiovascular diseases.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Molecular Medicine
Background:
- High-Density Lipoprotein (HDL) is crucial for reverse cholesterol transport.
- Myeloperoxidase (MPO), an inflammatory enzyme, modifies HDL, impairing its function and promoting atherosclerosis.
- Apolipoprotein A-I (apoA-I) is the primary protein in HDL, susceptible to MPO-mediated modifications.
Purpose of the Study:
- To investigate the in vivo effects of MPO on HDL structure and function.
- To explore the impact of specific apoA-I mutations on MPO-modified HDL.
- To assess the therapeutic potential of engineered HDL particles.
Main Methods:
- Adenovirus-mediated gene transfer of human MPO and modified human apoA-I in mice.
- Analysis of plasma HDL levels, size, and electrophoretic mobility.
- Assessment of HDL antioxidant capacity and cholesterol efflux from macrophages.
- Gene expression analysis in the liver.
Main Results:
- MPO overexpression increased plasma apoA-I and HDL levels without altering hepatic HDL gene expression.
- MPO overexpression reduced HDL's antioxidant capacity across all groups.
- The apoA-I (M148A) mutation altered HDL remodeling, while apoA-I (Y192A) enhanced cholesterol efflux independently of MPO.
- MPO overexpression in the liver decreased pro-inflammatory gene expression.
Conclusions:
- MPO influences HDL levels and antioxidant function, with specific apoA-I residues mediating distinct functional outcomes.
- Engineered apoA-I variants, like Y192A, demonstrate potential for enhanced cholesterol efflux and reduced LDL-c.
- Targeting apoA-I modifications offers a promising strategy for developing novel HDL-based therapies for chronic diseases.
