Abstract
Aims The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage angiotensin-converting enzyme (ACE) in a mouse model of PCSK9-induced atherosclerosis.
Methods and results Atherosclerosis in mice was induced with AAV-PCSK9 and a high-fat diet. Animals with increased macrophage ACE (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and have a profoundly altered phenotype to process lipids characterized by higher levels of the surface scavenger receptor CD36, increased uptake of lipid, increased capacity to transport long chain fatty acids into mitochondria, higher oxidative metabolism and lipid β-oxidation as determined using 13 C isotope tracing, increased cell ATP, increased capacity for efferocytosis, increased concentrations of the lipid transporters ABCA1 and ABCG1, and increased cholesterol efflux. These effects are mostly independent of angiotensin II. Human THP-1 cells, when modified to express more ACE, increase expression of PPARα, increase cell ATP and acetyl-CoA, and increase cell efferocytosis.
Conclusion Increased macrophage ACE expression enhances macrophage lipid metabolism, cholesterol efflux, efferocytosis, and it reduces atherosclerosis. This has implications for the treatment of cardiovascular disease with angiotensin II receptor antagonists vs. ACE inhibitors.
Document Type
Article
Publication Date
2023
Digital Object Identifier (DOI)
https://doi.org/10.1093/cvr/cvad082
Funding Information
This study was supported by AHA grants 23CDA1052548 (D.Y.C.), AHA grants 19CDA34760010 (Z.K.) and 16SDG30130015 (J.F.G.), NIH grant P01HL129941 (K.E.B.), R01AI134714 (K.E.B.), R01AI164519 (K.E.B.), R01HL142672 (J.F.G.), P30DK063491 (J.F.G.), K99HL141638 (D.O.-D.), R35 GM138003 (A.S.D.) and P30 DK063491 (A.S.D.). We thank Dr. Prediman K. Shah for the discussions concerning atherosclerosis. We also thank Dr. Aldons Jake Lusis (UCLA) and Sharda Charugundla for their discussions and help in measuring plasma lipid levels. The authors would also like to thank Daniel N. Leal, BS, CEMT for excellent assistance in per- forming electron microscopy.
Repository Citation
Cao, DuoYao; Khan, Zakir; Li, Xiaomo; Saito, Suguru; Bernstein, Ellen A.; Victor, Aaron R.; Ahmed, Faizan; Hoshi, Aoi O.; Veiras, Luciana C.; Shibata, Tomohiro; Che, Mingtian; Cai, Lei; Yamashita, Michifumi; Temel, Ryan E.; Giani, Jorge F.; Luthringer, Daniel J.; Divakaruni, Ajit S.; Okwan-Duodu, Derick; and Bernstein, Kenneth E., "Macrophage angiotensin-converting enzyme reduces atherosclerosis by increasing peroxisome proliferator-Activated receptor α and fundamentally changing lipid metabolism" (2023). Saha Cardiovascular Research Center Faculty Publications. 90.
https://uknowledge.uky.edu/cvrc_facpub/90
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Notes/Citation Information
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com