Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease
Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. Currently, the mechanism(s) by which inflammation contributes to this disease are not entirely understood. Inflammation is known to induce oxidative stress, which can lead to lipid peroxidation. Lipid peroxidation can...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/23/12948 |
| _version_ | 1797507693386137600 |
|---|---|
| author | Michael J. Duryee Dahn L. Clemens Patrick J. Opperman Geoffrey M. Thiele Logan M. Duryee Robert P. Garvin Daniel R. Anderson |
| author_facet | Michael J. Duryee Dahn L. Clemens Patrick J. Opperman Geoffrey M. Thiele Logan M. Duryee Robert P. Garvin Daniel R. Anderson |
| author_sort | Michael J. Duryee |
| collection | DOAJ |
| description | Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. Currently, the mechanism(s) by which inflammation contributes to this disease are not entirely understood. Inflammation is known to induce oxidative stress, which can lead to lipid peroxidation. Lipid peroxidation can result in the production of reactive by-products that can oxidatively modify macromolecules including DNA, proteins, and lipoproteins. A major reactive by-product of lipid peroxidation is malondialdehyde (MDA). MDA can subsequently break down to form acetaldehyde (AA). These two aldehydes can covalently interact with the epsilon (ε)-amino group of lysines within proteins and lipoproteins leading to the formation of extremely stable, highly immunogenic malondialdehyde/acetaldehyde adducts (MAA-adducts). The aim of this study was to investigate the inflammatory response to MAA-modified human serum albumin (HSA-MAA) and low-density lipoprotein (LDL-MAA). We found that animals injected with LDL-MAA generate antibodies specific to MAA-adducts. The level of anti-MAA antibodies were further increased in an animal model of atherosclerosis fed a Western diet. An animal model that combined both high fat diet and immunization of MAA-modified protein resulted in a dramatic increase in antibodies to MAA-adducts and vascular fat accumulation compared with controls. In vitro exposure of endothelial cells and macrophages to MAA-modified proteins resulted in increased fat accumulation as well as increased expression of adhesion molecules and pro-inflammatory cytokines. The expression of cytokines varied between the different cell lines and was unique to the individual modified proteins. The results of these studies demonstrate that different MAA-modified proteins elicit unique responses in different cell types. Additionally, the presence of MAA-modified proteins appears to modulate cellular metabolism leading to increased accumulation of triglycerides and further progression of the inflammatory response. |
| first_indexed | 2024-03-10T04:52:04Z |
| format | Article |
| id | doaj.art-31b866b8a10a40fa813097685ffd38f7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:04Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-31b866b8a10a40fa813097685ffd38f72023-11-23T02:30:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231294810.3390/ijms222312948Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular DiseaseMichael J. Duryee0Dahn L. Clemens1Patrick J. Opperman2Geoffrey M. Thiele3Logan M. Duryee4Robert P. Garvin5Daniel R. Anderson6Department of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USADepartment of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USADepartment of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USADepartment of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USADepartment of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USADepartment of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USADepartment of Internal Medicine, University of Nebraska Medical Center, 982650 Nebraska Medical Center, Omaha, NE 68198-2650, USAChronic inflammation plays a critical role in the pathogenesis of atherosclerosis. Currently, the mechanism(s) by which inflammation contributes to this disease are not entirely understood. Inflammation is known to induce oxidative stress, which can lead to lipid peroxidation. Lipid peroxidation can result in the production of reactive by-products that can oxidatively modify macromolecules including DNA, proteins, and lipoproteins. A major reactive by-product of lipid peroxidation is malondialdehyde (MDA). MDA can subsequently break down to form acetaldehyde (AA). These two aldehydes can covalently interact with the epsilon (ε)-amino group of lysines within proteins and lipoproteins leading to the formation of extremely stable, highly immunogenic malondialdehyde/acetaldehyde adducts (MAA-adducts). The aim of this study was to investigate the inflammatory response to MAA-modified human serum albumin (HSA-MAA) and low-density lipoprotein (LDL-MAA). We found that animals injected with LDL-MAA generate antibodies specific to MAA-adducts. The level of anti-MAA antibodies were further increased in an animal model of atherosclerosis fed a Western diet. An animal model that combined both high fat diet and immunization of MAA-modified protein resulted in a dramatic increase in antibodies to MAA-adducts and vascular fat accumulation compared with controls. In vitro exposure of endothelial cells and macrophages to MAA-modified proteins resulted in increased fat accumulation as well as increased expression of adhesion molecules and pro-inflammatory cytokines. The expression of cytokines varied between the different cell lines and was unique to the individual modified proteins. The results of these studies demonstrate that different MAA-modified proteins elicit unique responses in different cell types. Additionally, the presence of MAA-modified proteins appears to modulate cellular metabolism leading to increased accumulation of triglycerides and further progression of the inflammatory response.https://www.mdpi.com/1422-0067/22/23/12948atherosclerosisinflammationoxidative stressmalondialdehydeacetaldehydeprotein modification |
| spellingShingle | Michael J. Duryee Dahn L. Clemens Patrick J. Opperman Geoffrey M. Thiele Logan M. Duryee Robert P. Garvin Daniel R. Anderson Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease International Journal of Molecular Sciences atherosclerosis inflammation oxidative stress malondialdehyde acetaldehyde protein modification |
| title | Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease |
| title_full | Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease |
| title_fullStr | Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease |
| title_full_unstemmed | Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease |
| title_short | Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease |
| title_sort | malondialdehyde acetaldehyde modified maa proteins differentially effect the inflammatory response in macrophage endothelial cells and animal models of cardiovascular disease |
| topic | atherosclerosis inflammation oxidative stress malondialdehyde acetaldehyde protein modification |
| url | https://www.mdpi.com/1422-0067/22/23/12948 |
| work_keys_str_mv | AT michaeljduryee malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease AT dahnlclemens malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease AT patrickjopperman malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease AT geoffreymthiele malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease AT loganmduryee malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease AT robertpgarvin malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease AT danielranderson malondialdehydeacetaldehydemodifiedmaaproteinsdifferentiallyeffecttheinflammatoryresponseinmacrophageendothelialcellsandanimalmodelsofcardiovasculardisease |