{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:17:36Z","timestamp":1792084656234,"version":"4.4.0"},"reference-count":79,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-15-00065"],"award-info":[{"award-number":["21-15-00065"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.<\/jats:p>","DOI":"10.3390\/ijms25020689","type":"journal-article","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T05:12:17Z","timestamp":1704431537000},"page":"689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["iPSC-Derived Endothelial Cells Reveal LDLR Dysfunction and Dysregulated Gene Expression Profiles in Familial Hypercholesterolemia"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3643-5818","authenticated-orcid":false,"given":"Irina S.","family":"Zakharova","sequence":"first","affiliation":[{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander I.","family":"Shevchenko","sequence":"additional","affiliation":[{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2087-4202","authenticated-orcid":false,"given":"Mhd Amin","family":"Arssan","sequence":"additional","affiliation":[{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3226-1750","authenticated-orcid":false,"given":"Aleksei A.","family":"Sleptcov","sequence":"additional","affiliation":[{"name":"Research Institute of Medical Genetics, Tomsk National Research Medical Centre, Russian Academy of Science, 634050 Tomsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-4094","authenticated-orcid":false,"given":"Maria S.","family":"Nazarenko","sequence":"additional","affiliation":[{"name":"Research Institute of Medical Genetics, Tomsk National Research Medical Centre, Russian Academy of Science, 634050 Tomsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksei A.","family":"Zarubin","sequence":"additional","affiliation":[{"name":"Research Institute of Medical Genetics, Tomsk National Research Medical Centre, Russian Academy of Science, 634050 Tomsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina V.","family":"Zheltysheva","sequence":"additional","affiliation":[{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlada A.","family":"Shevchenko","sequence":"additional","affiliation":[{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3617-9343","authenticated-orcid":false,"given":"Narek A.","family":"Tmoyan","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, Ministry of Health of Russian Federation, 121552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoraan B.","family":"Saaya","sequence":"additional","affiliation":[{"name":"E.N. Meshalkin National Medical Research Centre, Ministry of Health Care of the Russian Federation, 630055 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-6552","authenticated-orcid":false,"given":"Marat V.","family":"Ezhov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, Ministry of Health of Russian Federation, 121552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valery V.","family":"Kukharchuk","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, Ministry of Health of Russian Federation, 121552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yelena V.","family":"Parfyonova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, Ministry of Health of Russian Federation, 121552 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suren M.","family":"Zakian","sequence":"additional","affiliation":[{"name":"Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1161\/ATVBAHA.108.179564","article-title":"The LDL Receptor","volume":"29","author":"Goldstein","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.atherosclerosis.2021.06.001","article-title":"LDLR Variants Functional Characterization: Contribution to Variant Classification","volume":"329","author":"Alves","year":"2021","journal-title":"Atherosclerosis"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Benito-Vicente, A., Uribe, K.B., Jebari, S., Galicia-Garcia, U., Ostolaza, H., and Martin, C. (2018). Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113426"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1016\/j.jacc.2020.03.057","article-title":"Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects","volume":"75","author":"Beheshti","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1016\/j.jacc.2020.03.058","article-title":"Familial Hypercholesterolemia: The Most Common Monogenic Disorder in Humans","volume":"75","author":"Kastelein","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","unstructured":"(2023, November 01). GWAS Catalog. Available online: https:\/\/www.ebi.ac.uk\/gwas\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1161\/CIRCRESAHA.118.313816","article-title":"Atherosclerosis a Chronic Inflammatory Disease with an Autoimmune Component","volume":"123","author":"Kobiyama","year":"2018","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"787541","DOI":"10.3389\/fphar.2021.787541","article-title":"Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights into Pathogenesis and Treatment","volume":"12","author":"Botts","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis","volume":"118","author":"Gimbrone","year":"2016","journal-title":"Circ. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1161\/CIRCULATIONAHA.119.044795","article-title":"Prevalence of Familial Hypercholesterolemia among the General Population and Patients with Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis","volume":"141","author":"Hu","year":"2020","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/s41569-023-00892-0","article-title":"International Atherosclerosis Society Guidance for Implementing Best Practice in the Care of Familial Hypercholesterolaemia","volume":"20","author":"Watts","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ganjali, S., Keshavarz, R., Hosseini, S., Mansouri, A., Mannarino, M.R., Pirro, M., Jamialahmadi, T., and Sahebkar, A. (2021). Evaluation of Oxidative Stress Status in Familial Hypercholesterolemia. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245867"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s11883-022-01023-9","article-title":"More than Just a Monolayer: The Multifaceted Role of Endothelial Cells in the Pathophysiology of Atherosclerosis","volume":"24","author":"Mussbacher","year":"2022","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nielsen, M.H., Irvine, H., Vedel, S., Raungaard, B., Beck-Nielsen, H., and Handberg, A. (2015). Elevated Atherosclerosis-Related Gene Expression, Monocyte Activation and Microparticle-Release Are Related to Increased Lipoprotein-Associated Oxidative Stress in Familial Hypercholesterolemia. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121516"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.ihj.2018.01.006","article-title":"Familial Hypercholesterolemia Supravalvular Aortic Stenosis and Extensive Atherosclerosis","volume":"70","author":"Prajapati","year":"2018","journal-title":"Indian Heart J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1016\/j.jacc.2015.09.087","article-title":"Increased Aortic Valve Calcification in Familial Hypercholesterolemia Prevalence, Extent, and Associated Risk Factors","volume":"66","author":"Bos","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"NP221","DOI":"10.1177\/2150135118783639","article-title":"Aortic Root Enlargement and Aortic Valve Replacement for Calcified Supravalvular and Valvular Aortic Stenosis in Homozygous Familial Hypercholesterolemia: A Case Report","volume":"11","author":"Chowdhury","year":"2020","journal-title":"World J. Pediatr. Congenit. Heart Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1093\/eurheartj\/ehaa1066","article-title":"Lipoprotein(a), LDL-Cholesterol, and Hypertension: Predictors of the Need for Aortic Valve Replacement in Familial Hypercholesterolaemia","volume":"42","author":"Watts","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.32607\/20758251-2010-2-2-18-27","article-title":"Induced Pluripotent Stem Cells: Problems and Advantages When Applying Them in Regenerative Medicine","volume":"2","author":"Medvedev","year":"2010","journal-title":"Acta Naturae"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"625016","DOI":"10.3389\/fcvm.2021.625016","article-title":"Development and Application of Endothelial Cells Derived From Pluripotent Stem Cells in Microphysiological Systems Models","volume":"8","author":"Kennedy","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1161\/ATVBAHA.117.309962","article-title":"Differentiation, Evaluation, and Application of Human Induced Pluripotent Stem Cell? Derived Endothelial Cells","volume":"37","author":"Lin","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.stemcr.2019.01.017","article-title":"Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human IPSC Model of Diabetic Endotheliopathy","volume":"12","author":"Ong","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.stemcr.2020.01.005","article-title":"IPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome","volume":"14","author":"Atchison","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.stemcr.2019.10.004","article-title":"Patient-Specific IPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures","volume":"13","author":"Kelleher","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jiang, B., Wang, X., Rivera-Bolanos, N., and Ameer, G.A. (2023). Generation of Autologous Vascular Endothelial Cells for Patients with Peripheral Artery Disease. J. Cardiovasc. Transl. Res., ahead of print.","DOI":"10.1007\/s12265-023-10452-z"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1186\/s13287-019-1342-6","article-title":"Low-Density Lipoprotein Receptor-Deficient Hepatocytes Differentiated from Induced Pluripotent Stem Cells Allow Familial Hypercholesterolemia Modeling, CRISPR\/Cas-Mediated Genetic Correction, and Productive Hepatitis C Virus Infection","volume":"10","author":"Caron","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/hep4.1110","article-title":"CRISPR Correction of a Homozygous Low-Density Lipoprotein Receptor Mutation in Familial Hypercholesterolemia Induced Pluripotent Stem Cells","volume":"1","author":"Omer","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"dmm042911","DOI":"10.1242\/dmm.042911","article-title":"Familial Hypercholesterolemia Class II Low-Density Lipoprotein Receptor Response to Statin Treatment","volume":"13","author":"Omer","year":"2020","journal-title":"DMM Dis. Model. Mech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.1038\/s41598-019-41056-w","article-title":"Function and Immunogenicity of Gene-Corrected IPSC-Derived Hepatocyte-Like Cells in Restoring Low Density Lipoprotein Uptake in Homozygous Familial Hypercholesterolemia","volume":"9","author":"Okada","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13231","DOI":"10.1038\/srep13231","article-title":"Restoration of Physiologically Responsive Low-Density Lipoprotein Receptor-Mediated Endocytosis in Genetically Deficient Induced Pluripotent Stem Cells","volume":"5","author":"Ramakrishnan","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1159\/000470829","article-title":"Microvascular Function and Endothelial Progenitor Cells in Patients with Severe Hypercholesterolemia and the Familial Hypercholesterolemia Phenotype","volume":"137","author":"Moreira","year":"2017","journal-title":"Cardiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104216","DOI":"10.1016\/j.mvr.2021.104216","article-title":"Assessment of Microvascular Function and Pharmacological Regulation in Genetically Confirmed Familial Hypercholesterolemia","volume":"138","author":"Pajkowski","year":"2021","journal-title":"Microvasc. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2199218","DOI":"10.1080\/07853890.2023.2199218","article-title":"Coronary Microcirculatory Dysfunction in Hypercholesterolemic Patients with COVID-19: Potential Benefit from Cholesterol-Lowering Treatment","volume":"55","author":"Vuorio","year":"2023","journal-title":"Ann. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Catar, R., Chen, L., Zhao, H., Wu, D., Kamhieh-Milz, J., L\u00fccht, C., Zickler, D., Krug, A.W., Ziegler, C.G., and Morawietz, H. (2022). Native and Oxidized Low-Density Lipoproteins Increase the Expression of the LDL Receptor and the LOX-1 Receptor, Respectively, in Arterial Endothelial Cells. Cells, 11.","DOI":"10.3390\/cells11020204"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1111\/bph.15272","article-title":"LDL Receptors, Caveolae and Cholesterol in Endothelial Dysfunction: OxLDLs Accomplices or Victims?","volume":"178","author":"Luchetti","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3389\/fcvm.2018.00130","article-title":"Endothelial Transcytosis of Lipoproteins in Atherosclerosis","volume":"5","author":"Zhang","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1083\/jcb.138.4.877","article-title":"A New Function for the LDL Receptor: Transcytosis of LDL across the Blood-Brain Barrier","volume":"138","author":"Dehouck","year":"1997","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"102703","DOI":"10.1016\/j.scr.2022.102703","article-title":"Induced Pluripotent Stem Cell Line ICGi037-A, Obtained by Reprogramming Peripheral Blood Mononuclear Cells from a Patient with Familial Hypercholesterolemia Due to Heterozygous p.Trp443Arg Mutations in LDLR","volume":"60","author":"Zakharova","year":"2022","journal-title":"Stem Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102653","DOI":"10.1016\/j.scr.2022.102653","article-title":"Induced Pluripotent Stem Cell Line ICGi036-A Generated by Reprogramming Peripheral Blood Mononuclear Cells from a Patient with Familial Hypercholesterolemia Caused Due to Compound Heterozygous p.Ser177Leu\/p.Cys352Arg Mutations in LDLR","volume":"59","author":"Zakharova","year":"2022","journal-title":"Stem Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nazarenko, M.S., Sleptcov, A.A., Zarubin, A.A., Salakhov, R.R., Shevchenko, A.I., Tmoyan, N.A., Elisaphenko, E.A., Zubkova, E.S., Zheltysheva, N.V., and Ezhov, M.V. (2023). Calling and Phasing of Single-Nucleotide and Structural Variants of the LDLR Gene Using Oxford Nanopore MinION. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054471"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/282615a0","article-title":"Controlled Synthesis of HBsAg in a Differentiated Human Liver Carcinoma-Derived Cell Line","volume":"282","author":"Aden","year":"1979","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"570355","DOI":"10.3389\/fgene.2020.570355","article-title":"Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia","volume":"11","author":"Oommen","year":"2020","journal-title":"Front. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Thormaehlen, A.S., Schuberth, C., Won, H.H., Blattmann, P., Joggerst-Thomalla, B., Theiss, S., Asselta, R., Duga, S., Merlini, P.A., and Ardissino, D. (2015). Systematic Cell-Based Phenotyping of Missense Alleles Empowers Rare Variant Association Studies: A Case for LDLR and Myocardial Infarction. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1004855"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1038\/s41598-020-58734-9","article-title":"Mutation Type Classification and Pathogenicity Assignment of Sixteen Missense Variants Located in the EGF-Precursor Homology Domain of the LDLR","volume":"10","author":"Uribe","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Semenova, A.E., Sergienko, I.V., Garc\u00eda-Giustiniani, D., Monserrat, L., Popova, A.B., Nozadze, D.N., and Ezhov, M.V. (2020). Verification of Underlying Genetic Cause in a Cohort of Russian Patients with Familial Hypercholesterolemia Using Targeted next Generation Sequencing. J. Cardiovasc. Dev. Dis., 7.","DOI":"10.3390\/jcdd7020016"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Meshkov, A., Ershova, A., Kiseleva, A., Zotova, E., Sotnikova, E., Petukhova, A., Zharikova, A., Malyshev, P., Rozhkova, T., and Blokhina, A. (2021). The Ldlr, Apob, and Pcsk9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. Genes, 12.","DOI":"10.3390\/genes12010066"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1097\/MOL.0000000000000114","article-title":"PCSK9 and LDLR Degradation: Regulatory Mechanisms in Circulation and in Cells","volume":"25","author":"Lagace","year":"2014","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"764038","DOI":"10.3389\/fcvm.2021.764038","article-title":"Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications","volume":"8","author":"Xia","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5420","DOI":"10.1074\/jbc.TM117.000832","article-title":"Metabolism in Pluripotency: Both Driver and Passenger?","volume":"294","author":"Dahan","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s12944-019-1120-6","article-title":"Fatty Acids, Epigenetic Mechanisms and Chronic Diseases: A Systematic Review","volume":"18","author":"Milagro","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"100941","DOI":"10.1016\/j.molmet.2020.01.005","article-title":"Compartmentalised Acyl-CoA Metabolism and Roles in Chromatin Regulation","volume":"38","author":"Trefely","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1271\/bbb.67.856","article-title":"Transepithelial Transport of Ferulic Acid by Monocarboxylic Acid Transporter in Caco-2 Cell Monolayers","volume":"67","author":"Konishi","year":"2003","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/MOH.0000000000000332","article-title":"Rap1 in Endothelial Biology","volume":"24","year":"2017","journal-title":"Curr. Opin. Hematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"920","DOI":"10.4049\/jimmunol.173.2.920","article-title":"Rap1 Signaling Is Required for Suppression of Ras-Generated Reactive Oxygen Species and Protection Against Oxidative Stress in T Lymphocytes","volume":"173","author":"Remans","year":"2004","journal-title":"J. Immunol."},{"key":"ref_55","first-page":"127","article-title":"Xanthine Dehydrogenase\/Xanthine Oxldase and Oxidative Stress","volume":"20","author":"Chung","year":"1997","journal-title":"J. Am. Aging Assoc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1161\/ATVBAHA.120.315401","article-title":"Endothelial Rap1 (Ras-Association Proximate 1) Restricts Inflammatory Signaling to Protect from the Progression of Atherosclerosis","volume":"41","author":"Singh","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1161\/ATVBAHA.112.301155","article-title":"Endothelial Expression of Guidance Cues in Vessel Wall Homeostasis Dysregulation under Proatherosclerotic Conditions","volume":"33","author":"Ramkhelawon","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1101\/gad.320077.118","article-title":"Synaptotagmin-11 Mediates a Vesicle Trafficking Pathway That Is Essential for Development and Synaptic Plasticity","volume":"33","author":"Shimojo","year":"2019","journal-title":"Genes Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41398-021-01223-y","article-title":"Cntn4, a Risk Gene for Neuropsychiatric Disorders, Modulates Hippocampal Synaptic Plasticity and Behavior","volume":"11","author":"Bamford","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1002\/glia.23186","article-title":"Synaptotagmin-11 Inhibits Cytokine Secretion and Phagocytosis in Microglia","volume":"65","author":"Du","year":"2017","journal-title":"Glia"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.21037\/atm-22-3768","article-title":"MiR-148a-3p Attenuates Apoptosis and Inflammation by Targeting CNTN4 in Atherosclerosis","volume":"10","author":"Wang","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Jeon, B.-N., Kim, S., Kim, Y., Yu, H., Kim, H., Ha, Y., Kim, Y.Y., Park, C., Kim, G., and Cha, M. (2023). CNTN4\/APP Axis of Cancer Cells and T-Cells. PREPRINT (Version 1). Res. Sq., preprint.","DOI":"10.21203\/rs.3.rs-2979573\/v1"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"734550","DOI":"10.3389\/fcvm.2021.734550","article-title":"Endothelial to Mesenchymal Transition: An Insight in Atherosclerosis","volume":"8","author":"Huang","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/S0735-1097(03)00994-X","article-title":"The Clinical Implications of Endothelial Dysfunction","volume":"42","author":"Widlansky","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1083\/jcb.201412052","article-title":"Recent Insights into the Cellular Biology of Atherosclerosis","volume":"209","author":"Tabas","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/joim.13580","article-title":"The Red Blood Cell as a Mediator of Endothelial Dysfunction in Patients with Familial Hypercholesterolemia and Dyslipidemia","volume":"293","author":"Mahdi","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1111\/bph.13517","article-title":"Targeting Vascular (Endothelial) Dysfunction","volume":"174","author":"Daiber","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Little, P.J., Askew, C.D., Xu, S., and Kamato, D. (2021). Endothelial Dysfunction and Cardiovascular Disease: History and Analysis of the Clinical Utility of the Relationship. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060699"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s00246-013-0742-0","article-title":"Endothelial Dysfunction, but Not Structural Atherosclerosis, Is Evident Early in Children with Heterozygous Familial Hypercholesterolemia","volume":"35","author":"Vlahos","year":"2014","journal-title":"Pediatr. Cardiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"101952","DOI":"10.1016\/j.scr.2020.101952","article-title":"Generation of Induced Pluripotent Stem Cell Lines ICGi021-A and ICGi022-A from Peripheral Blood Mononuclear Cells of Two Healthy Individuals from Siberian Population","volume":"48","author":"Malakhova","year":"2020","journal-title":"Stem Cell Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e64","DOI":"10.1002\/cphg.64","article-title":"Efficient Differentiation of Human Pluripotent Stem Cells to Endothelial Cells","volume":"98","author":"Gu","year":"2018","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1134\/S1062360423020054","article-title":"Chemokine CCL2 Activates Hypoxia Response Factors Regulating Pluripotency and Directed Endothelial Differentiation of Human Pluripotent Stem Cells","volume":"54","author":"Shevchenko","year":"2023","journal-title":"Russ. J. Dev. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12967-017-1156-1","article-title":"Endothelial and Smooth Muscle Cells Derived from Human Cardiac Explants Demonstrate Angiogenic Potential and Suitable for Design of Cell-Containing Vascular Grafts","volume":"15","author":"Zakharova","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zakharova, I., Saaya, S., Shevchenko, A., Stupnikova, A., Zhiven\u2019, M., Laktionov, P., Stepanova, A., Romashchenko, A., Yanshole, L., and Chernonosov, A. (2022). Mitomycin-Treated Endothelial and Smooth Muscle Cells Suitable for Safe Tissue Engineering Approaches. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.772981"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1089\/scd.2015.0204","article-title":"Transcriptome Characteristics and X-Chromosome Inactivation Status in Cultured Rat Pluripotent Stem Cells","volume":"24","author":"Vaskova","year":"2015","journal-title":"Stem Cells Dev."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zudaire, E., Gambardella, L., Kurcz, C., and Vermeren, S. (2011). A Computational Tool for Quantitative Analysis of Vascular Networks. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027385"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: Summarize Analysis Results for Multiple Tools and Samples in a Single Report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_78","first-page":"1438","article-title":"From Reads to Genes to Pathways: Differential Expression Analysis of RNA-Seq Experiments Using Rsubread and the EdgeR Quasi-Likelihood Pipeline","volume":"5","author":"Chen","year":"2016","journal-title":"F1000Research"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/689\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:40:18Z","timestamp":1760103618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,5]]},"references-count":79,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25020689"],"URL":"https:\/\/doi.org\/10.3390\/ijms25020689","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,5]]}}}