{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:59:17Z","timestamp":1790812757477,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIDDK NIH HHS\/United States","award":["R01 DK116768"],"award-info":[{"award-number":["R01 DK116768"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Apoe-deficient (Apoe\u2212\/\u2212) and Ldlr-deficient (Ldlr\u2212\/\u2212) mice are two common animal models of hypercholesterolemia and atherosclerosis. The two models differ in lipid and glucose metabolism and other mechanisms involved in atherogenesis. Here we examined atherosclerotic lesion formation in the two models with an atherosclerosis-resistant C3H\/HeJ (C3H) background. 3-month-old C3H-Ldlr\u2212\/\u2212 and C3H-Apoe\u2212\/\u2212 mice developed minimal atherosclerotic lesions in the aortic root when fed a chow diet. After 12 weeks on a Western diet, C3H-Ldlr\u2212\/\u2212 mice developed 3-fold larger lesions than C3H-Apoe\u2212\/\u2212 mice in the aortic root (127,386 \u00b1 13,439 vs. 41,542 \u00b1 5075 \u03bcm2\/section; p = 0.00028), but neither knockout formed any lesion in the carotid artery. After being ligated near its bifurcation, the common carotid artery developed intimal lesions in both knockouts 4 weeks after ligation, significantly larger in C3H-Ldlr\u2212\/\u2212 than C3H-Apoe\u2212\/\u2212 mice (68,721 \u00b1 2706 vs. 47,472 \u00b1 8146 \u03bcm2\/section; p = 0.028). Compared to C3H-Apoe\u2212\/\u2212 mice, C3H-Ldlr\u2212\/\u2212 mice showed a 50% reduction in plasma MCP-1 levels, similar levels of malondialdehyde, an oxidative stress biomarker, on both chow and Western diets, but higher small dense LDL levels on the Western diet. These results suggest a more significant role for small dense LDL than inflammation and oxidative stress in the different susceptibility of the mouse models to atherosclerosis.<\/jats:p>","DOI":"10.3390\/cells12091255","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T04:42:54Z","timestamp":1682484174000},"page":"1255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Atherogenesis in Apoe\u2212\/\u2212 and Ldlr\u2212\/\u2212 Mice with a Genetically Resistant Background"],"prefix":"10.3390","volume":"12","author":[{"given":"Hideyuki","family":"Torikai","sequence":"first","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jin","sequence":"additional","affiliation":[{"name":"Orthopedic Surgery, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7600-4604","authenticated-orcid":false,"given":"Jiang","family":"He","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Angle","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-613X","authenticated-orcid":false,"given":"Weibin","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"ref_1","unstructured":"(2022, December 31). The Top 10 Causes of Death. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/the-top-10-causes-of-death."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1001\/jama.294.3.326","article-title":"Non-HDL Cholesterol, Apolipoproteins A-I and B100, Standard Lipid Measures, Lipid Ratios, and CRP as Risk Factors for Cardiovascular Disease in Women","volume":"294","author":"Ridker","year":"2005","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1161\/hc3501.095214","article-title":"Coronary Heart Disease Prediction from Lipoprotein Cholesterol Levels, Triglycerides, Lipoprotein(a), Apolipoproteins A-I and B, and HDL Density Subfractions: The Atherosclerosis Risk in Communities (ARIC) Study","volume":"104","author":"Sharrett","year":"2001","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1038\/s41591-022-01891-3","article-title":"Large-Scale Genome-Wide Association Study of Coronary Artery Disease in Genetically Diverse Populations","volume":"28","author":"Tcheandjieu","year":"2022","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.atherosclerosissup.2004.08.027","article-title":"Randomised Trial of Cholesterol Lowering in 4444 Patients with Coronary Heart Disease: The Scandinavian Simvastatin Survival Study (4S)","volume":"5","author":"Pedersen","year":"2004","journal-title":"Atheroscler. Suppl."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4330\/wjc.v9.i2.76","article-title":"PCSK9 Inhibitors: A New Era of Lipid Lowering Therapy","volume":"9","author":"Chaudhary","year":"2017","journal-title":"World J. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1016\/j.jacc.2017.10.024","article-title":"Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors","volume":"70","author":"Fuster","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Shi, W., Li, J., Bao, K., Chen, M.-H., and Liu, Z. (2022). Ldlr-Deficient Mice with an Atherosclerosis-Resistant Background Develop Severe Hyperglycemia and Type 2 Diabetes on a Western-Type Diet. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061429"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1172\/JCI10695","article-title":"Defining the Atherogenicity of Large and Small Lipoproteins Containing Apolipoprotein B100","volume":"106","author":"Sullivan","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, S., Li, J., Chen, M.H., Liu, Z., and Shi, W. (2015). Variation in Type 2 Diabetes-Related Phenotypes among Apolipoprotein E-Deficient Mouse Strains. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120935"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.bbrc.2006.04.180","article-title":"Hyperlipidemia Is a Major Determinant of Neointimal Formation in LDL Receptor-Deficient Mice","volume":"345","author":"Tian","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1161\/ATVBAHA.116.306874","article-title":"Do the Apoe\u2212\/\u2212 and Ldlr\u2212\/\u2212 Mice Yield the Same Insight on Atherogenesis?","volume":"36","author":"Getz","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1161\/01.ATV.16.8.1013","article-title":"Lymphocyte Populations in Atherosclerotic Lesions of ApoE \u2212\/\u2212 and LDL Receptor \u2212\/\u2212 Mice","volume":"16","author":"Roselaar","year":"1996","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1161\/01.ATV.20.3.846","article-title":"Atherosclerosis Progression in LDL Receptor\u2013Deficient and Apolipoprotein E\u2013Deficient Mice Is Independent of Genetic Alterations in Plasminogen Activator Inhibitor-1","volume":"20","author":"Eitzman","year":"2000","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e14829","DOI":"10.14814\/phy2.14829","article-title":"Inflammation and Enhanced Atherogenesis in the Carotid Artery with Altered Blood Flow in an Atherosclerosis-Resistant Mouse Strain","volume":"9","author":"Zhao","year":"2021","journal-title":"Physiol. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1159\/000502691","article-title":"Atherogenesis in the Carotid Artery with and without Interrupted Blood Flow of Two Hyperlipidemic Mouse Strains","volume":"56","author":"Zhao","year":"2019","journal-title":"J. Vasc. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1161\/01.CIR.102.1.75","article-title":"Endothelial Responses to Oxidized Lipoproteins Determine Genetic Susceptibility to Atherosclerosis in Mice","volume":"102","author":"Shi","year":"2000","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"iyab160","DOI":"10.1093\/genetics\/iyab160","article-title":"Identification of Mep1a as a Susceptibility Gene for Atherosclerosis in Mice","volume":"219","author":"Grainger","year":"2021","journal-title":"Genetics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"110289","DOI":"10.18632\/oncotarget.22685","article-title":"Accelerated Atherogenesis in Completely Ligated Common Carotid Artery of Apolipoprotein E-Deficient Mice","volume":"8","author":"Chang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1194\/jlr.D300007-JLR200","article-title":"A Novel and Simple Method for Quantification of Small, Dense LDL","volume":"44","author":"Hirano","year":"2003","journal-title":"J. Lipid. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1093\/clinchem\/hvab048","article-title":"A New Equation Based on the Standard Lipid Panel for Calculating Small Dense Low-Density Lipoprotein-Cholesterol and Its Use as a Risk-Enhancer Test","volume":"67","author":"Sampson","year":"2021","journal-title":"Clin. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1161\/01.ATV.0000090126.34881.B1","article-title":"Induction of Atherosclerosis by Low-Fat, Semisynthetic Diets in LDL Receptor-Deficient C57BL\/6J and FVB\/NJ Mice: Comparison of Lesions of the Aortic Root, Brachiocephalic Artery, and Whole Aorta (En Face Measurement)","volume":"23","author":"Teupser","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ma, Y., Wang, W., Zhang, J., Lu, Y., Wu, W., Yan, H., and Wang, Y. (2012). Hyperlipidemia and Atherosclerotic Lesion Development in Ldlr-Deficient Mice on a Long-Term High-Fat Diet. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035835"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"H1535","DOI":"10.1152\/ajpheart.00510.2009","article-title":"Partial Carotid Ligation Is a Model of Acutely Induced Disturbed Flow, Leading to Rapid Endothelial Dysfunction and Atherosclerosis","volume":"297","author":"Nam","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1172\/JCI116495","article-title":"Genetic Control of Inflammatory Gene Induction and NF-Kappa B-like Transcription Factor Activation in Response to an Atherogenic Diet in Mice","volume":"91","author":"Liao","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Tanaka, T., Oyama, T., Sugie, S., and Shimizu, M. (2016). Different Susceptibilities between Apoe- and Ldlr-Deficient Mice to Inflammation-Associated Colorectal Carcinogenesis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17111806"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/s41591-018-0336-8","article-title":"ApoE Attenuates Unresolvable Inflammation by Complex Formation with Activated C1q","volume":"25","author":"Yin","year":"2019","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1089\/jir.2008.0027","article-title":"Monocyte chemoattractant protein-1 (MCP-1): An overview","volume":"29","author":"Deshmane","year":"2009","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1161\/01.ATV.20.4.1020","article-title":"Apolipoprotein E Inhibition of Vascular Smooth Muscle Cell Proliferation but Not the Inhibition of Migration Is Mediated Through Activation of Inducible Nitric Oxide Synthase","volume":"20","author":"Ishigami","year":"2000","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2019.11.034","article-title":"Genetic linkage of oxidative stress with cardiometabolic traits in an intercross derived from hyperlipidemic mouse strains","volume":"293","author":"Fuller","year":"2019","journal-title":"Atherosclerosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"360438","DOI":"10.1155\/2014\/360438","article-title":"Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal","volume":"2014","author":"Ayala","year":"2014","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0002-9343(00)00700-2","article-title":"Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins","volume":"110","author":"Tribble","year":"2001","journal-title":"Am. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.bbrc.2004.12.137","article-title":"The role of apolipoprotein E in the elimination of liposomes from blood by hepatocytes in the mouse","volume":"328","author":"Yan","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5810","DOI":"10.1073\/pnas.86.15.5810","article-title":"Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins","volume":"86","author":"Kowal","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1172\/JCI116663","article-title":"Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery","volume":"92","author":"Ishibashi","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1016\/S0022-2275(20)32173-8","article-title":"Resistance of chylomicron and VLDL remnants to post-heparin lipolysis in ApoE-deficient mice: The role of apoE in lipoprotein lipase-mediated lipolysis in vivo and in vitro","volume":"39","author":"Zsigmond","year":"1998","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1016\/S0002-9440(10)65045-6","article-title":"Strain-Dependent Vascular Remodeling Phenotypes in Inbred Mice","volume":"156","author":"Harmon","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1161\/01.ATV.17.11.2333","article-title":"Atherosclerosis, Vascular Remodeling, and Impairment of Endothelium-Dependent Relaxation in Genetically Altered Hyperlipidemic Mice","volume":"17","author":"Bonthu","year":"1997","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1161\/01.ATV.17.10.2238","article-title":"Remodeling with Neointima Formation in the Mouse Carotid Artery After Cessation of Blood Flow","volume":"17","author":"Kumar","year":"1997","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1161\/01.ATV.0000091249.34404.B7","article-title":"Genetic Backgrounds but Not Sizes of Atherosclerotic Lesions Determine Medial Destruction in the Aortic Root of Apolipoprotein E\u2013Deficient Mice","volume":"23","author":"Shi","year":"2003","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1161\/hc0802.104327","article-title":"Relationship Between Coronary Artery Remodeling and Plaque Vulnerability","volume":"105","author":"Varnava","year":"2002","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1093\/ehjci\/jev221","article-title":"The influence of lipid-containing plaque composition assessed by near-infrared spectroscopy on coronary lesion remodelling","volume":"17","author":"Ota","year":"2015","journal-title":"Eur. Hear. J. Cardiovasc. Imaging"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/9\/1255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:23:45Z","timestamp":1760124225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/9\/1255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,26]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12091255"],"URL":"https:\/\/doi.org\/10.3390\/cells12091255","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,26]]}}}