Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease
Abstract
1. Introduction
2. Results
2.1. Proteins on LDL Are MAA Adducted
2.2. MAA Modified LDL Is Immunogenic
2.3. LDL-MAA Increases Fat Accumulation in Vascular Endothelial Cells
2.4. MAA Adducted Proteins Increase Adhesion Molecules and Cytokines in Vascular Endothelial Cells
2.5. LDL-MAA Increases Fat Accumulation in Mouse Macrophage
2.6. MAA-Modified Proteins Increase Pro-Inflammatory Cytokines in Macrophage
2.7. High Fat Diet and MAA Antigen Increase Aortic Fat Deposition (Key Finding)
3. Discussion
4. Materials and Methods
4.1. Malondialdehyde-Acetaldehyde (MAA)-Protein Adduct Formation
4.2. Animal Studies
4.3. Cell Culture
4.4. Detection of Cellular Lipids
4.5. RT-PCR
4.6. Flow Cytometry
4.7. Immunohistochemistry
4.8. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Benjamin, E.J.; Blaha, M.J.; Chiuve, S.E.; Cushman, M.; Das, S.R.; Deo, R.; de Ferranti, S.D.; Floyd, J.; Fornage, M.; Gillespie, C.; et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation 2017, 135, e146–e603. [Google Scholar] [CrossRef] [PubMed]
- Hansson, G.K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 2005, 352, 1685–1695. [Google Scholar] [CrossRef] [PubMed]
- Libby, P. Inflammation in atherosclerosis. Nature 2002, 420, 868–874. [Google Scholar] [CrossRef]
- Ross, R. Atherosclerosis--an inflammatory disease. N. Engl. J. Med. 1999, 340, 115–126. [Google Scholar] [CrossRef]
- Madamanchi, N.R.; Hakim, Z.S.; Runge, M.S. Oxidative stress in atherogenesis and arterial thrombosis: The disconnect between cellular studies and clinical outcomes. J. Thromb. Haemost 2005, 3, 254–267. [Google Scholar] [CrossRef] [PubMed]
- Madamanchi, N.R.; Vendrov, A.; Runge, M.S. Oxidative stress and vascular disease. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 29–38. [Google Scholar] [CrossRef] [PubMed]
- Kunsch, C.; Medford, R.M. Oxidative stress as a regulator of gene expression in the vasculature. Circ. Res. 1999, 85, 753–766. [Google Scholar] [CrossRef]
- Spychalowicz, A.; Wilk, G.; Sliwa, T.; Ludew, D.; Guzik, T.J. Novel therapeutic approaches in limiting oxidative stress and inflammation. Curr. Pharm. Biotechnol. 2012, 13, 2456–2466. [Google Scholar] [CrossRef]
- Ayala, A.; Munoz, M.F.; Arguelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid. Med. Cell Longev. 2014, 2014, 360438. [Google Scholar] [CrossRef] [PubMed]
- Esterbauer, H.; Schaur, R.J.; Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 1991, 11, 81–128. [Google Scholar] [CrossRef]
- Gaschler, M.M.; Stockwell, B.R. Lipid peroxidation in cell death. Biochem. Biophys. Res. Commun. 2017, 482, 419–425. [Google Scholar] [CrossRef] [PubMed]
- Binder, C.J.; Chang, M.K.; Shaw, P.X.; Miller, Y.I.; Hartvigsen, K.; Dewan, A.; Witztum, J.L. Innate and acquired immunity in atherogenesis. Nat. Med. 2002, 8, 1218–1226. [Google Scholar] [CrossRef]
- Binder, C.J.; Papac-Milicevic, N.; Witztum, J.L. Innate sensing of oxidation-specific epitopes in health and disease. Nat. Rev. Immunol. 2016, 16, 485–497. [Google Scholar] [CrossRef] [PubMed]
- Kikugawa, K.; Ido, Y. Studies on peroxidized lipids. V. Formation and characterization of 1,4-dihydropyridine-3,5-dicarbaldehydes as model of fluorescent components in lipofuscin. Lipids 1984, 19, 600–608. [Google Scholar] [CrossRef] [PubMed]
- Tuma, D.J.; Thiele, G.M.; Xu, D.; Klassen, L.W.; Sorrell, M.F. Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration. Hepatology 1996, 23, 872–880. [Google Scholar] [CrossRef] [PubMed]
- Thiele, G.M.; Tuma, D.J.; Willis, M.S.; Miller, J.A.; McDonald, T.L.; Sorrell, M.F.; Klassen, L.W. Soluble proteins modified with acetaldehyde and malondialdehyde are immunogenic in the absence of adjuvant. Alcohol. Clin. Exp. Res. 1998, 22, 1731–1739. [Google Scholar] [CrossRef]
- Xu, D.; Thiele, G.M.; Kearley, M.L.; Haugen, M.D.; Klassen, L.W.; Sorrell, M.F.; Tuma, D.J. Epitope characterization of malondialdehyde-acetaldehyde adducts using an enzyme-linked immunosorbent assay. Chem. Res. Toxicol. 1997, 10, 978–986. [Google Scholar] [CrossRef] [PubMed]
- Willis, M.S.; Klassen, L.W.; Carlson, D.L.; Brouse, C.F.; Thiele, G.M. Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage. Int. Immunopharmacol. 2004, 4, 885–899. [Google Scholar] [CrossRef]
- Willis, M.S.; Thiele, G.M.; Tuma, D.J.; Klassen, L.W. T cell proliferative responses to malondialdehyde-acetaldehyde haptenated protein are scavenger receptor mediated. Int. Immunopharmacol. 2003, 3, 1381–1399. [Google Scholar] [CrossRef]
- Anderson, D.R.; Duryee, M.J.; Shurmur, S.W.; Um, J.Y.; Bussey, W.D.; Hunter, C.D.; Garvin, R.P.; Sayles, H.R.; Mikuls, T.R.; Klassen, L.W.; et al. Unique antibody responses to malondialdehyde-acetaldehyde (MAA)-protein adducts predict coronary artery disease. PLoS ONE 2014, 9, e107440. [Google Scholar] [CrossRef]
- Duryee, M.J.; Klassen, L.W.; Schaffert, C.S.; Tuma, D.J.; Hunter, C.D.; Garvin, R.P.; Anderson, D.R.; Thiele, G.M. Malondialdehyde-acetaldehyde adduct is the dominant epitope after MDA modification of proteins in atherosclerosis. Free Radic. Biol. Med. 2010, 49, 1480–1486. [Google Scholar] [CrossRef] [PubMed]
- Libby, P.; Ridker, P.M.; Hansson, G.K. Progress and challenges in translating the biology of atherosclerosis. Nature 2011, 473, 317–325. [Google Scholar] [CrossRef] [PubMed]
- Viola, J.; Soehnlein, O. Atherosclerosis-A matter of unresolved inflammation. Semin. Immunol. 2015, 27, 184–193. [Google Scholar] [CrossRef] [PubMed]
- Steinberg, D.; Parthasarathy, S.; Carew, T.E.; Khoo, J.C.; Witztum, J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 1989, 320, 915–924. [Google Scholar] [CrossRef]
- Hill, G.E.; Miller, J.A.; Baxter, B.T.; Klassen, L.W.; Duryee, M.J.; Tuma, D.J.; Thiele, G.M. Association of malondialdehyde-acetaldehyde (MAA) adducted proteins with atherosclerotic-induced vascular inflammatory injury. Atherosclerosis 1998, 141, 107–116. [Google Scholar] [CrossRef]
- Fotis, L.; Agrogiannis, G.; Vlachos, I.S.; Pantopoulou, A.; Margoni, A.; Kostaki, M.; Verikokos, C.; Tzivras, D.; Mikhailidis, D.P.; Perrea, D. Intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 at the early stages of atherosclerosis in a rat model. In Vivo 2012, 26, 243–250. [Google Scholar] [PubMed]
- Moss, J.W.; Ramji, D.P. Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets. Future Med. Chem. 2016, 8, 1317–1330. [Google Scholar] [CrossRef]
- Stocker, R.; Keaney, J.F., Jr. Role of oxidative modifications in atherosclerosis. Physiol. Rev. 2004, 84, 1381–1478. [Google Scholar] [CrossRef]
- Anderson, D.R.; Duryee, M.J.; Anchan, R.K.; Garvin, R.P.; Johnston, M.D.; Porter, T.R.; Thiele, G.M.; Klassen, L.W. Albumin-based microbubbles bind up-regulated scavenger receptors following vascular injury. J. Biol. Chem. 2010, 285, 40645–40653. [Google Scholar] [CrossRef]
- Duryee, M.J.; Willis, M.S.; Freeman, T.L.; Kuszynski, C.A.; Tuma, D.J.; Klassen, L.W.; Thiele, G.M. Mechanisms of alcohol liver damage: Aldehydes, scavenger receptors, and autoimmunity. Front. Biosci. 2004, 9, 3145–3155. [Google Scholar] [CrossRef]
- Thiele, G.M.; Duryee, M.J.; Hunter, C.D.; England, B.R.; Fletcher, B.S.; Daubach, E.C.; Pospisil, T.P.; Klassen, L.W.; Mikuls, T.R. Immunogenic and inflammatory responses to citrullinated proteins are enhanced following modification with malondialdehyde-acetaldehyde adducts. Int. Immunopharmacol. 2020, 83, 106433. [Google Scholar] [CrossRef] [PubMed]
- Ashraf, M.Z.; Sahu, A. Scavenger receptors: A key player in cardiovascular diseases. Biomol. Concepts. 2012, 3, 371–380. [Google Scholar] [CrossRef][Green Version]
- Moore, K.J.; Freeman, M.W. Scavenger receptors in atherosclerosis: Beyond lipid uptake. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 1702–1711. [Google Scholar] [CrossRef]
- Clemens, D.L.; Duryee, M.J.; Hall, J.H.; Thiele, G.M.; Mikuls, T.R.; Klassen, L.W.; Zimmerman, M.C.; Anderson, D.R. Relevance of the antioxidant properties of methotrexate and doxycycline to their treatment of cardiovascular disease. Pharmacol. Ther. 2020, 205, 107413. [Google Scholar] [CrossRef] [PubMed]
- Schneider, C.A.; Rasband, W.S.; Eliceiri, K.W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 2012, 9, 671–675. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Duryee, M.J.; Clemens, D.L.; Opperman, P.J.; Thiele, G.M.; Duryee, L.M.; Garvin, R.P.; Anderson, D.R. Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease. Int. J. Mol. Sci. 2021, 22, 12948. https://doi.org/10.3390/ijms222312948
Duryee MJ, Clemens DL, Opperman PJ, Thiele GM, Duryee LM, Garvin RP, Anderson DR. 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. 2021; 22(23):12948. https://doi.org/10.3390/ijms222312948
Chicago/Turabian StyleDuryee, Michael J., Dahn L. Clemens, Patrick J. Opperman, Geoffrey M. Thiele, Logan M. Duryee, Robert P. Garvin, and Daniel R. Anderson. 2021. "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 22, no. 23: 12948. https://doi.org/10.3390/ijms222312948
APA StyleDuryee, M. J., Clemens, D. L., Opperman, P. J., Thiele, G. M., Duryee, L. M., Garvin, R. P., & Anderson, D. R. (2021). 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, 22(23), 12948. https://doi.org/10.3390/ijms222312948