{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T17:54:45Z","timestamp":1781373285824,"version":"3.54.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Epigenetics was reported to mediate the effects of environmental risk factors on disease pathogenesis. We intend to unleash the role of DNA methylation modification in the pathological process of cardiovascular diseases in diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We screened differentially methylated genes by methylated DNA immunoprecipitation chip (MeDIP-chip) among the enrolled participants. In addition, methylation-specific PCR (MSP) and gene expression validation in peripheral blood of participants were utilized to validate the DNA microarray findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Several aberrantly methylated genes have been explored, including phospholipase C beta 1 (PLCB1), cam kinase I delta (CAMK1D), and dopamine receptor D5 (DRD5), which participated in the calcium signaling pathway. Meanwhile, vascular endothelial growth factor B (VEGFB), placental growth factor (PLGF), fatty acid transport protein 3 (FATP3), coagulation factor II, thrombin receptor (F2R), and fatty acid transport protein 4 (FATP4) which participated in vascular endothelial growth factor receptor (VEGFR) signaling pathway were also found. After MSP and gene expression validation in peripheral blood of participants, PLCB1, PLGF, FATP4, and VEGFB were corroborated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study revealed that the hypomethylation of VEGFB, PLGF, PLCB1, and FATP4 might be the potential biomarkers. Besides, VEGFR signaling pathway regulated by DNA methylation might play a role in the cardiovascular diseases\u2019 pathogenesis of diabetes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1108126","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T09:16:43Z","timestamp":1676452603000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["DNA methylation profiling reveals novel pathway implicated in cardiovascular diseases of diabetes"],"prefix":"10.3389","volume":"14","author":[{"given":"Shengqing","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianshu","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangli","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0140-6736(11)60679-X","article-title":"National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants","volume":"378","author":"Danaei","year":"2011","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000033824.02722.F7","article-title":"Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function","volume":"106","author":"Cruickshank","year":"2002","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"697240","DOI":"10.1155\/2012\/697240","article-title":"Diabetes and coronary heart disease: a risk factor for the global epidemic","volume":"2012","author":"Chiha","year":"2012","journal-title":"Int J hypertension"},{"key":"B4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s11886-019-1133-9","article-title":"Mortality and cardiovascular disease in type 1 and type 2 diabetes","volume":"21","author":"Htay","year":"2019","journal-title":"Curr Cardiol Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/db09-1216","article-title":"Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT\/EDIC: comparison of adults and adolescents","volume":"59","author":"White","year":"2010","journal-title":"Diabetes"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052187","article-title":"Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes","author":"Nathan","year":"2005","journal-title":"New Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.12.017","article-title":"NADPH oxidase 4 and endothelial nitric oxide synthase contribute to endothelial dysfunction mediated by histone methylations in metabolic memory","volume":"115","author":"Liao","year":"2018","journal-title":"Free Radical Biol Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"BSR20160611","DOI":"10.1042\/BSR20160611","article-title":"Novel insights into DNA methylation and its critical implications in diabetic vascular complications","volume":"37","author":"Zheng","year":"2017","journal-title":"Biosci Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1007\/s11892-015-0677-3","article-title":"Epigenetics and cardiovascular disease in diabetes","volume":"15","author":"Pasquier","year":"2015","journal-title":"Curr Diabetes Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2011.05497.x","article-title":"Epigenetics: deciphering its role in diabetes and its chronic complications","volume":"38","author":"Villeneuve","year":"2011","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000357824","article-title":"Epigenetic mechanisms in the pathogenesis of diabetic retinopathy","volume":"232","author":"Zeng","year":"2014","journal-title":"Ophthalmol J Int d\u2019ophtalmol Int J Ophthalmol Z fur Augenheilkunde"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12521","article-title":"DNA Methylation and its role in the pathogenesis of diabetes","volume":"18","author":"Bansal","year":"2017","journal-title":"Pediatr Diabetes"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI74792","article-title":"Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis","volume":"124","author":"Dunn","year":"2014","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122601","article-title":"A comparison of genome-wide DNA methylation patterns between different vascular tissues from patients with coronary heart disease","volume":"10","author":"Nazarenko","year":"2015","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s12916-017-0792-x","article-title":"Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects","volume":"15","author":"Davegardh","year":"2017","journal-title":"BMC Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.305298","article-title":"DNA Methylation indicates susceptibility to isoproterenol-induced cardiac pathology and is associated with chromatin states","volume":"118","author":"Chen","year":"2016","journal-title":"Circ Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.546283","article-title":"Epigenetic modulation of intestinal cholesterol transporter niemann-pick C1-like 1 (NPC1L1) gene expression by DNA methylation","volume":"289","author":"Malhotra","year":"2014","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S","article-title":"Definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation","volume":"15","author":"Alberti","year":"1998","journal-title":"Diabetic medicine: J Br Diabetic Assoc"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(06)11014-9","article-title":"Statistics for ChIP-chip and DNase hypersensitivity experiments on NimbleGen arrays","volume":"411","author":"Scacheri","year":"2006","journal-title":"Methods enzymol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology","volume-title":"Nat Genet","author":"Ashburner","year":"2000"},{"key":"B22","doi-asserted-by":"publisher","first-page":"R183","DOI":"10.1186\/gb-2007-8-9-r183","article-title":"The DAVID gene functional classification tool: a novel biological module-centric algorithm to functionally analyze large gene lists","volume":"8","author":"Huang","year":"2007","journal-title":"Genome Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1155\/2004\/370301","article-title":"Methylation-specific PCR unraveled","volume":"26","author":"Derks","year":"2004","journal-title":"Cell Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat Protoc"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1006\/scdb.2000.0211","article-title":"Calcium signalling\u2013an overview","volume":"12","author":"Bootman","year":"2001","journal-title":"Semin Cell Dev Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.atherosclerosis.2010.06.038","article-title":"Differential expression of genes in the calcium-signaling pathway underlies lesion development in the LDb mouse model of atherosclerosis","volume":"213","author":"Mak","year":"2010","journal-title":"Atherosclerosis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01095.2008","article-title":"Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility","volume":"296","author":"Yuan","year":"2009","journal-title":"Am J Physiol Heart Circulatory Physiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/86490","article-title":"Vascular endothelial growth factor enhances atherosclerotic plaque progression","volume":"7","author":"Celletti","year":"2001","journal-title":"Nat Med"},{"key":"B29","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1056\/NEJMoa012512","article-title":"Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin","volume":"346","author":"Knowler","year":"2002","journal-title":"New Engl J Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nature18642","article-title":"The genetic architecture of type 2 diabetes","volume":"536","author":"Fuchsberger","year":"2016","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/MCO.0000000000000177","article-title":"Developmental programming of type 2 diabetes: early nutrition and epigenetic mechanisms","volume":"18","author":"Ong","year":"2015","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403618200","article-title":"DNA Methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein e","volume":"279","author":"Lund","year":"2004","journal-title":"J Biol Chem"},{"key":"B33","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1186\/s12916-015-0421-5","article-title":"Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy","volume":"13","author":"Agardh","year":"2015","journal-title":"BMC Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/ng.298","article-title":"The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores","volume":"41","author":"Irizarry","year":"2009","journal-title":"Nat Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-010-1967-6","article-title":"Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets","volume":"54","author":"Yang","year":"2011","journal-title":"Diabetologia"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036278","article-title":"Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes","volume":"7","author":"Fradin","year":"2012","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-014-3462-y","article-title":"Epigenetic mechanisms in diabetic complications and metabolic memory","volume":"58","author":"Reddy","year":"2015","journal-title":"Diabetologia"},{"key":"B38","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s12866-020-01762-2","article-title":"Multi-omic profiling reveals associations between the gut mucosal microbiome, the metabolome, and host DNA methylation associated gene expression in patients with colorectal cancer","volume":"20","author":"Wang","year":"2020","journal-title":"BMC Microbiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-06-0141","article-title":"Down-regulation of placenta growth factor by promoter hypermethylation in human lung and colon carcinoma","volume":"5","author":"Xu","year":"2007","journal-title":"Mol Cancer res: MCR"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.2003924","article-title":"The palliative effects of folic acid on retinal microvessels in diabetic retinopathy via regulating the metabolism of DNA methylation and hydroxymethylation","volume":"12","author":"Liu","year":"2021","journal-title":"Bioengineered"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-015-1115-7","article-title":"Methylation patterns of vegfb promoter are associated with gene and protein expression levels: the effects of dietary fatty acids","volume":"56","author":"Monastero","year":"2015","journal-title":"Eur J Nutr"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s11154-013-9239-7","article-title":"Endothelial dysfunction in (pre)diabetes: characteristics, causative mechanisms and pathogenic role in type 2 diabetes","volume":"14","author":"Eringa","year":"2013","journal-title":"Rev endocr Metab Disord"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1097\/MCA.0000000000000178","article-title":"Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment","volume":"25","author":"Matsuzawa","year":"2014","journal-title":"Coronary artery Dis"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000178991.71605.18","article-title":"Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage","volume":"25","author":"Virmani","year":"2005","journal-title":"Arteriosclerosis thrombosis Vasc Biol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00706","article-title":"Vasa vasorum angiogenesis: Key player in the initiation and progression of atherosclerosis and potential target for the treatment of cardiovascular disease","volume":"9","author":"Sedding","year":"2018","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-008-9114-4","article-title":"The discovery of the placental growth factor and its role in angiogenesis: a historical review","volume":"11","author":"Ribatti","year":"2008","journal-title":"Angiogenesis"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201303147","article-title":"VEGF-b-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart","volume":"6","author":"Kivela","year":"2014","journal-title":"EMBO Mol Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.03.004","article-title":"VEGFB\/VEGFR1-induced expansion of adipose vasculature counteracts obesity and related metabolic complications","volume":"23","author":"Robciuc","year":"2016","journal-title":"Cell Metab"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nature08945","article-title":"Vascular endothelial growth factor b controls endothelial fatty acid uptake","volume":"464","author":"Hagberg","year":"2010","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nature11464","article-title":"Targeting VEGF-b as a novel treatment for insulin resistance and type 2 diabetes","volume":"490","author":"Hagberg","year":"2012","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1177\/2040622314529325","article-title":"The emerging role of epigenetics in cardiovascular disease","volume":"5","author":"Abi Khalil","year":"2014","journal-title":"Ther Adv Chronic Dis"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1108126\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T09:16:48Z","timestamp":1676452608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1108126\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,15]]},"references-count":52,"alternative-id":["10.3389\/fendo.2023.1108126"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1108126","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,15]]},"article-number":"1108126"}}