Dietary Restriction Reduces Atherosclerosis and Oxidative Stress in the Aorta of Apolipoprotein E-Deficient Mice
Abstract
Dietary restriction (DR) has been shown to inhibit almost all the age-related diseases, e.g. cardiomyopathy and cancers, in rodents. However, there is little information for the effect of DR on atherosclerosis. In the present study, we examined the effect of DR on the development of atherosclerosis in mice homozygous knockout for apolipoprotein E gene (ApoE(-/-)). The ApoE(-/-) mice were fed either ad libitum (AL) or 60% of the diet consumed by the mice fed AL. Atherosclerotic lesions in the proximal aorta of these mice were measured. Our results showed that ApoE(-/-) mice fed the calorie-restricted diet had smaller and relatively early stages of atherosclerotic lesions (e.g. foam cells and free lipids) when compared to ApoE(-/-) mice fed AL, who developed more advanced lesions (e.g. fibrous caps and acellular areas). In addition, ApoE(-/-) mice fed the calorie-restricted diet showed a significant decrease in the level of lipid hydroperoxides and the production of superoxide and hydrogen peroxide in the aorta as compared to ApoE(-/-) mice fed AL. These observations suggest that reduction of oxidative stress in the arterial wall may contribute to the anti-atherogenic effect of DR in ApoE(-/-) mice.
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Apart from lifespan extension, caloric restriction reduces risk factors for major diseases including diabetes and cardiovascular disease in rodents.
“Apart from lifespan extension, caloric restriction also reduces the risk factors for major diseases including diabetes and cardiovascular disease in rodents (209, 210).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [209]
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Noncoding RNAs in age-related cardiovascular diseases
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“The proximal aorta attached to the heart was used to prepare cross-sections, as described previously [18].”
MethodInfluentialCalorie restriction protects against experimental abdominal aortic aneurysms in mice
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“Consistent with previous studies (Guo et al., 2002; McCurdy and Cartee, 2005; Boily et al., 2008), in our mouse model, we observed that CR affected systemic metabolic indices by decreasing BW, EE, and RQ and improving glucose regulatory function.”
ResultLuo, X.-Y., Qu, S.-L., Tang, Z., Zhang, Y. E., Liu, M., Peng, J., Tang, H. R., Yu, K., Zhang, C., Ren, Z., et al. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.07.019 · Cited by 72 · see citing works
Calorie restriction and cardiometabolic health
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“This is further validated by SIRT1 activation or calorie restriction in ApoE mice leads to protection against atherosclerosis progression by upregulating eNOS [43-45].”
Backgroundde Lucia, C., Gambino, G., Petraglia, L., Elia, A., Komici, K., Femminella, G. D., D’Amico, M. L., Formisano, R., Borghetti, G., Liccardo, D., et al. (2018) · Circulation Heart Failure · doi:10.1161/circheartfailure.117.004153 · Cited by 64 · see citing works
Brain response to calorie restriction
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“This fundamental, cell-autonomous mechanism affects nearly all cells and tissues of the body, and likely participates in the beneficial CR action on a wide range of chronic diseases, including diabetes, cancer, cardiovascular, autoimmune, and neurodegenerative diseases in rodents [16–19].”
BackgroundMetabotyping of Long-Lived Mice using 1H NMR Spectroscopy
Wijeyesekera, A., Selman, C., Barton, R. H., Holmes, E. C., Nicholson, J. K., & Withers, D. J. (2012) · Journal of Proteome Research · doi:10.1021/pr2010154 · Cited by 60 · see citing works
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“erols, increase HDL, and retard the development of atherosclerosis (40).”
BackgroundEpigenetic Regulation of Vascular Aging and Age-Related Vascular Diseases
Ding, Y.-N., Tang, X., Chen, H., & Liu, D. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_4 · Cited by 55 · see citing works
Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction
Muralimanoharan, S., Li, C., Nakayasu, E. S., Casey, C., Metz, T., Nathanielsz, P. W., & Maloyan, A. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.06.006 · Cited by 51 · see citing works
Caloric restriction and heart function: is there a sensible link?
Han, X., & Ren, J. T. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.146 · Cited by 51 · see citing works
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“Under anesthesia, the mice were perfusion-fixed with 4% paraformaldehyde containing 20 μM butylated hydroxytoluene and 2 μM EDTA at a constant, near-physiological pressure (80 mmHg) (15).”
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Vascular aging and cardiovascular disease: pathophysiology and measurement in the coronary arteries
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Energy restriction and potential energy restriction mimetics
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“In the past, chronic diseases like type 2 diabetes mellitus (T2DM), hypertension, CVD and cancer were mostly observed in the elderly.”
InfluentialDietary Interventions, Cardiovascular Aging, and Disease
Mirzaei, H., Biase, S. D., & Longo, V. D. (2016) · Circulation Research · doi:10.1161/circresaha.116.307473 · Cited by 39 · see citing works
“CR also attenuates the formation of atherosclerotic plaques and results in lower levels of reactive oxygen species and lipid hydroperoxide (a marker for oxidative damage) in the aorta.(75) by gest on Sptem er 5, 2017 http://circhajournals.”
BackgroundWang, Z., Yang, H., Ramesh, A., Roberts, L. J., Zhou, L., Lin, X., Zhao, Y., & Guo, Z. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.08.001 · Cited by 37 · see citing works
“The cumulative O2 concentration was calculated based on a standard curve generated by incubation of lucigenin with xanthine/xanthine oxidase [14].”
MethodAge-related cardiovascular disease and the beneficial effects of calorie restriction
Sung, M. M. Y., & Dyck, J. R. B. (2011) · Heart Failure Reviews · doi:10.1007/s10741-011-9293-8 · Cited by 37 · see citing works
“[71] have shown that CR (40% CR for 19 weeks) retards the progression of atherosclerotic lesion formation in apolipoprotein E knockout mice.”
BackgroundKudchodkar, B. J., Pierce, A. P., & Dory, L. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.08.018 · Cited by 36 · see citing works
Li, D., Chen, A., Lan, T., Zou, Y., Zhao, L., Yang, P., Qu, H., Li, W., Varghese, Z., Moorhead, J. F., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201800975rrr · Cited by 34 · see citing works
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Attenuation of leukocyte-endothelium interaction by antioxidant enzymes
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Vafa, M., & Hanjani, N. (2018) · International Journal of Preventive Medicine · doi:10.4103/ijpvm.ijpvm_397_16 · Cited by 33 · see citing works
“Mice homozygous knockout for the apolipoprotein E gene (ApoE−/−) under a calorie‐restricted regimen (60% of total calorie) had fewer formations of atherosclerotic lesions in relatively early stages compared to the AL group.[18] Endothelial dysfunction and vascular oxidative stress due to obesity have been reversed by…”
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“These observations suggest that a reduction of oxidative stress in the arterial wall may be involved in the anti-atherogenic effect of energy restriction (72).”
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Paradoxical reduction of atherosclerosis in apoE-deficient mice with obesity-related type 2 diabetes
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Dietary Restriction and Oxidative Stress: Friends or Enemies?
Mladenović, A., Lončarević‐Vasiljković, N., & Gonos, E. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7959 · Cited by 27 · see citing works
“…effect of DR on atherosclerosis, plaque deposition, hypertension, and other cardiovascular complications is exerted via the modulation of the activity of both SIRT1 and AMPK (48, 64, 106) whose activity reduces ROS generation (28, 35) and improves mitochondrial biogenesis and function (156).”
García‐Prieto, C. F., Gil‐Ortega, M., Plaza, A., Manzano-Lista, F. J., González‐Blázquez, R., Alcalá, M., Rodríguez‐Rodríguez, P., Viana, M., Aránguez, I., Gollasch, M., et al. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.05.016 · Cited by 24 · see citing works
Zinc finger E‐box binding homeobox 1 and atherosclerosis: New insights and therapeutic potential
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Dieta Intermitente Atenua a Remodelação Cardíaca Causada pelo Exercício Físico
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Food with calorie restriction reduces the development of atherosclerosis in apoE-deficient mice
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The impacts of different dietary restriction regimens on aging and longevity: from yeast to humans
Ching, T., & Hsu, A. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01188-w · Cited by 15 · see citing works
Molecular mechanisms of calorie restriction's protection against age-related sclerosis
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“A 40% calorie restriction was shown to reduce the dimension and progression of atherosclerotic lesions in the aorta of Apo-E-deficient mice in parallel to a decrease in oxidative stress parameters ( 71 ).”
BackgroundO efeito da restrição calórica na longevidade
Genaro, P. D. S., Sarkis, K. S., & Martini, L. A. (2009) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302009000500019 · Cited by 11 · see citing works
Mechanistic perspectives of calorie restriction on vascular homeostasis
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Inflammation in Aging Processes
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Calorie restriction in mice does not affect LDL reverse cholesterol transport in vivo
Stein, O. T., Dabach, Y., Halperin, G., Ben-Naim, M., & Stein, Y. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01313-5 · Cited by 8 · see citing works
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“, Melville, NY), as described previously [11].”
BackgroundMethodChen, A., & Yang, L. Z. H. (2010) · Journal of Bioanalysis & Biomedicine · doi:10.4172/1948-593x.1000031 · Cited by 7 · see citing works
“Similarly, mice deficient in ApoE gene (ApoE-/-) or mice expressing ApoB48 but lacking ApoE and ApoB100 (ApoE-/-/B48/48) develop hypercholesterolemia due to increased ApoB48-carrying lipoproteins (Piedrahita et al., 1992; Guo et al., 2002; Farese et al., 1996).”
BackgroundMethodEffects of age and caloric restriction on the cardiac and coronary response to endothelin-1 in rats
Granado, M., Rubio, C., Amor, S., Monge, L., Fernández, N., Carreño‐Tarragona, G., Carrascosa, J. M., & Garcı́a-Villalón, Á. L. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.10.018 · Cited by 6 · see citing works
“Dietary restriction has beneficial effects on the cardiovascular system which seems to be mediated, at least in part, by an attenuation of the agerelated increase in inflammation (Guo et al., 2002) and oxidative stress (Sohal and Weindruch, 1996).”
BackgroundDietary factors in atherogenesis
Wilson, M. G., & Thomas, D. R. (2003) · Current Atherosclerosis Reports · doi:10.1007/s11883-003-0056-4 · Cited by 6 · see citing works
“ApoE-deficient mice on a low-calorie and oxysterol-poor diet exhibit a reduction in lipid hydroperoxide content and reactive molecular oxygen generation within the arterial wall [ 17 ].”
Chevli, P. A., Mirzai, S., Kazibwe, R., Kingsley, J., Wood, A. C., Yeboah, J., Slipczuk, L. N., Mehta, A., Bhatia, H. S., Pandey, A., et al. (2026) · Journal of the American Heart Association · doi:10.1161/jaha.125.042582 · Cited by 5 · see citing works
“25,26 These findings underscore the complex and possibly context-dependent role of KBs in cardiometabolic health.”
Lapenna, D., Ciofani, G., Cuccurullo, C., Neri, M., Giamberardino, M. A., & Cuccurullo, F. (2012) · Free Radical Research · doi:10.3109/10715762.2012.719613 · Cited by 5 · see citing works
“Regarding vascular H 2 O 2 , it is overproduced at levels in the hundreds of micromolar range in dyslipidemia and hypertension [19,20].”
BackgroundCoronary atherosclerosis: Significance of autophagic armour
Arora, M. (2012) · World Journal of Cardiology · doi:10.4330/wjc.v4.i9.271 · Cited by 5 · see citing works
Shimba, Y., Senda, R., Katayama, K., Morita, A., Ikeda, M., Kamei, Y., & Miura, S. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.01.001 · Cited by 4 · see citing works
CHRONIC LITHIUM TREATMENT PREVENT ANXIETY-LIKE BEHAVIOR RELATED TO DIETARY RESTRICTION
Ferreira, F. R., Spini, V. B. M. G., Ribeiro, G. D. C. C., & Paduani, G. F. (2009) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · Cited by 4 · see citing works
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“evidence of atherogenic effects of EC-SOD and CuZnSOD in hyperlipidemic conditions [29,30], which notably induce vascular H2O2 overproduction [31].”
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“Likewise, ApoE-deficient (ApoE / ) mice manifest elevated plasma ApoB48-containing lipoproteins and develop atherosclerosis in a manner that resembles the human disease (Piedrahita et al., 1992; Guo et al., 2002).”
BackgroundCaloric Restriction and Cardiovascular Disease
Csiszár, A., de Cabo, R., & Ungvari, Z. I. (2010) · Springer eBooks · doi:10.1007/978-90-481-8556-6_15 · Cited by 4 · see citing works
Intense Caloric Restriction from Birth Prevents Cardiovascular Aging in Rats
Melo, D. D. S., Pereira, L. C., SANTOS, C. D. S., Mendes, B. F., Konig, I. F. M., Garcia, B. C. C., Queiroz, I. P., Moreno, L. G., Cassilhas, R. C., Esteves, E. A., et al. (2023) · Rejuvenation Research · doi:10.1089/rej.2023.0032 · Cited by 3 · see citing works
- Authors
- Guo, Z., Mitchell-Raymundo, F., Yang, H., Ikeno, Y., Nelson, J., Diaz, V., Richardson, A., & Reddick, R.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Guo, ZhongMao
- Venue
- Mechanisms of Ageing and Development
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 123
- Issue
- 8
- Pages
- 1121-1131
- ISSN
- 0047-6374 (ISSN-L)
- OpenAlex
- W2034827383
- Cited by
- 121
- References
- 60
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 6 · 2013: 7 · 2012: 8
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mechanisms of Ageing and Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute on Aging (AG16998, P01 AG-13319, R01AG016998)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- dietary restriction, caloric restriction, atherosclerosis, ApoE-deficient mice, oxidative stress, lipid peroxidation, superoxide, hydrogen peroxide, aortic lesions, foam cells, antiatherogenic effects, aging
- MeSH terms
- Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Energy Intake, Cholesterol, Diet, Disease Models, Animal, Hydrogen Peroxide, Lipoproteins, LDL, Male, Superoxides, Lipid Peroxidation, Mice, Knockout, Oxidative Stress, Mice
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