The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis
Open accessAbstract
RATIONALE: Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. OBJECTIVE: We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways. METHODS AND RESULTS: In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1-mediated cholesterol efflux. Specifically, anti-miR33 derepressed the novel target genes PGC-1α, PDK4, and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe(-/-) mice with anti-miR33 oligonucleotides reduced aortic sinus lesion area compared with controls, despite no changes in high-density lipoprotein cholesterol or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared with normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1α, SLC25A25, NRF1, and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans. CONCLUSIONS: This study demonstrates that anti-miR33 therapy derepresses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis.
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“Inhibition of miR-33a or miR-33a deletion in macrophages has been shown to affect myeloid cell differentiation 25) , induce M2 macrophage polarization with mitochondrial respiratory and metabolic changes 26 , 27) , and enhance autophagy 28 , 29) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [27]
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“several studies have found that antagonism of miR-33 can reduce atherosclerotic plaque burden (Karunakaran et al., 2015; Ouimet et al., 2015; Rayner et al., 2011b; Rotllan et al., 2013).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Karunakaran et al., 2015
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Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479
Macrophages in the Pathogenesis of Atherosclerosis
Moore, K. J., & Tabas, I. (2011) · Cell · doi:10.1016/j.cell.2011.04.005 · Cited by 2,669
Self-citationPGC-1 coactivators: inducible regulators of energy metabolism in health and disease
Finck, B. N. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27794 · Cited by 1,461
HDL cholesterol efflux capacity and incident cardiovascular events
Rohatgi, A., Khera, A., Berry, J. D., Givens, E. G., Ayers, C. R., Wedin, K. E., Neeland, I. J., Yuhanna, I. S., Rader, D. R., de Lemos, J. A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409065 · Cited by 1,390
Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
Vats, D., Mukundan, L., Odegaard, J. I., Zhang, L., Smith, K. L., Morel, C. R., Greaves, D. R., Murray, P. J., & Chawla, A. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.05.011 · Cited by 1,369
MiR-33 Contributes to the Regulation of Cholesterol Homeostasis
Rayner, K. J., Suárez, Y., Dávalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., & Fernández-Hernando, C. (2010) · Science · doi:10.1126/science.1189862 · Cited by 1,260
Self-citationHandschin, C., & Spiegelman, B. M. (2006) · Endocrine Reviews · doi:10.1210/er.2006-0037 · Cited by 1,090
The role of exercise and PGC1α in inflammation and chronic disease
Handschin, C., & Spiegelman, B. M. (2008) · Nature · doi:10.1038/nature07206 · Cited by 1,083
MicroRNA-33 and the SREBP Host Genes Cooperate to Control Cholesterol Homeostasis
Najafi-Shoushtari, S. H., Kristo, F., Li, Y., Shioda, T., Cohen, D. E., Gerszten, R. E., & Näär, A. M. (2010) · Science · doi:10.1126/science.1189123 · Cited by 957
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Self-citationMetabolism of tissue macrophages in homeostasis and pathology
Wculek, S. K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A., & Sancho, D. (2022) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00791-9 · Cited by 501
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Zhong, S., Li, L., Shen, X., Li, Q., Xu, W., Wang, X., Tao, Y., & Yin, H. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.03.036 · Cited by 342
Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis
Wculek, S. K., Heras‐Murillo, I., Mastrangelo, A., Mañanes, D., Galán, M. Á., Miguel, V., Curtabbi, A., Barbas, C., Chandel, N. S., Enrı́quez, J. A., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.01.011 · Cited by 315
Mapping macrophage polarization over the myocardial infarction time continuum
Mouton, A. J., DeLeon‐Pennell, K. Y., Gonzalez, O. J. R., Flynn, E. R., Freeman, T. C., Saucerman, J. J., Garrett, M. R., Ma, Y., Harmancey, R., & Lindsey, M. L. (2018) · Basic Research in Cardiology · doi:10.1007/s00395-018-0686-x · Cited by 317
Metadata
- Authors
- Karunakaran, D., Thrush, A. B., Nguyen, M.-A., Richards, L., Geoffrion, M., Singaravelu, R., Ramphos, E., Shangari, P., Ouimet, M., Pezacki, J. P., Moore, K. J., Perisic, L., Maegdefessel, L., Hedin, U., Harper, M.-E., & Rayner, K. J.
- Affiliations
- University of Ottawa (CA)
- From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada (D.K., M.-A.N., L.R., M.G., E.R., P.S., K.J.R.); Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada (A.B.T., M.-A.N., R.S., J.P.P., M.-E.H., K.J.R.); National Research Council of Canada, Ottawa, Ontario, Canada (R.S., J.P.P.); Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine (M.O., K...
- ORCID
- Venue
- Circulation Research
- Published
- 2015-07-17
- Volume
- 117
- Issue
- 3
- Pages
- 266-278
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4578799
- OpenAlex
- W2171031572
- Cited by
- 188
- References
- 46
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 14 · 2023: 17 · 2022: 19 · 2021: 21 · 2020: 13 · 2019: 18 · 2018: 18 · 2017: 15 · 2016: 26 · 2015: 6
- FWCI
- 21.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- NPARC (submittedVersion)
- Funders
- University of Ottawa
- Hjärt-Lungfonden
- Canadian Institutes of Health Research (30365_1, OCN126572)
- National Heart, Lung, and Blood Institute (R01HL119047, R01HL108182)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- miR-33, macrophage cholesterol efflux, atherosclerosis, mitochondrial bioenergetics, ATP synthase, ABCA1, PGC-1α, mitochondrial respiration, foam cells, ApoE-deficient mice, carotid plaque, reverse cholesterol transport
- MeSH terms
- Adenosine Triphosphate, Animals, Apolipoproteins E, Base Sequence, Calcium-Binding Proteins, Cell Line, Cholesterol, Gene Expression Regulation, Humans, Macrophages, Mice, Inbred C57BL, Mitochondria, Sequence Homology, Nucleic Acid, Transcription Factors, Genetic Therapy, Oligonucleotides, Antisense, Sequence Alignment, Protein Serine-Threonine Kinases, Macrophages, Peritoneal, Amino Acid Transport Systems, Acidic, Mitochondrial Membrane Transport Proteins, MicroRNAs, Atherosclerosis, Mice, HEK293 Cells
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