{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T07:43:01Z","timestamp":1762674181135,"version":"3.41.2"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,4,5]]},"abstract":"\n Background<\/jats:title>\n \n Peripheral vascular disease is a major diabetes mellitus\u2010related complication. In this study, we noted that expressions of proapoptotic p53 gene and its downstream cascade gene such as p21 are upregulated in hyperglycemia. Therefore, we investigated whether p53\u2010 and p21\u2010silenced endothelial progenitor cells (\n EPC<\/jats:styled-content>\n s) were able to survive in hyperglycemic milieu, and whether transplantation of either p53 knockout (KO) or p21\n KO<\/jats:styled-content>\n or p53\u2010 and p21\u2010silenced\n EPC<\/jats:styled-content>\n s could improve collateral vessel formation and blood flow in diabetic vaso\u2010occlusive peripheral vascular disease mouse models.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n We transplanted p53 and p21\n KO<\/jats:styled-content>\n mouse\n EPC<\/jats:styled-content>\n s (\n mEPC<\/jats:styled-content>\n s) into streptozotocin\u2013induced diabetic (type 1 diabetes mellitus model) C57\n BL<\/jats:styled-content>\n \/6J and db\/db (B6.\n BKS<\/jats:styled-content>\n (D)\u2010Leprdb\/J) (type 2 model) post\u2013femoral artery occlusion. Similarly, Ad\u2010p53\u2013silenced and Ad\u2010p21\u2013silenced human\n EPC<\/jats:styled-content>\n s (\n CD<\/jats:styled-content>\n 34+) cells were transplanted into streptozotocin\u2010induced diabetic\n NOD<\/jats:styled-content>\n .\n CB<\/jats:styled-content>\n 17\u2010Prkdcscid\/J mice. We measured blood flow at 3, 7, and 10\u00a0days and hindlimb muscles were obtained postsacrifice for\n mRNA<\/jats:styled-content>\n estimation and\n CD<\/jats:styled-content>\n 31 staining. Enhanced blood flow was noted with delivery of p53 and p21\n KO mEPC<\/jats:styled-content>\n s in\n streptozotocin<\/jats:styled-content>\n \u2010induced diabetic C57\n BL<\/jats:styled-content>\n \/6J mice. Similar results were obtained when human Ad\u2010p53sh\n EPC<\/jats:styled-content>\n s(\n CD<\/jats:styled-content>\n 34+) and Ad\u2010p21sh\n EPC<\/jats:styled-content>\n s(\n CD<\/jats:styled-content>\n 34+) were transplanted into streptozotocin\u2010induced nonobese diabetic severe combined immunodeficiency mice. Gene expression analysis of p53 and p21\n KO EPC<\/jats:styled-content>\n s transplanted hindlimb muscles showed increased expression of endothelial markers such as endothelial nitric oxide synthase, vascular endothelial growth factor A, and platelet endothelial cell adhesion molecule 1. Similarly, quantitative reverse transcriptase polymerase chain reaction of human Ad\u2010p53sh\n EPC<\/jats:styled-content>\n s (\n CD<\/jats:styled-content>\n 34+)\u2013 and Ad\u2010p21sh\n EPC<\/jats:styled-content>\n s (\n CD<\/jats:styled-content>\n 34+)\u2013transplanted hindlimb muscles also showed increased expression of endothelial markers such as vascular endothelial growth factor A, noted primarily in the p53\u2010silenced\n EPC<\/jats:styled-content>\n s group. However, such beneficial effect was not noted in the db\/db type 2 diabetic mouse models.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Transient silencing of p53 using adenoviral vector in\n EPC<\/jats:styled-content>\n s may have a therapeutic role in diabetic peripheral vascular disease.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.116.005146","type":"journal-article","created":{"date-parts":[[2017,4,2]],"date-time":"2017-04-02T00:25:33Z","timestamp":1491092733000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Use of p53\u2010Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease"],"prefix":"10.1161","volume":"6","author":[{"given":"Nabanita","family":"Kundu","sequence":"first","affiliation":[{"name":"Department of Medicine, The George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cleyton C.","family":"Domingues","sequence":"additional","affiliation":[{"name":"Department of Medicine, The George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cyril","family":"Chou","sequence":"additional","affiliation":[{"name":"Pioneer Valley Life Science Institute, Baystate Medical Center, Springfield, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeki","family":"Ahmadi","sequence":"additional","affiliation":[{"name":"Department of Medicine, The George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Houston","sequence":"additional","affiliation":[{"name":"Department of Medicine, The George Washington University, Washington, DC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. Joseph","family":"Jerry","sequence":"additional","affiliation":[{"name":"Pioneer Valley Life Science Institute, Baystate Medical Center, Springfield, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabyasachi","family":"Sen","sequence":"additional","affiliation":[{"name":"Department of Medicine, The George Washington University, Washington, DC"},{"name":"Pioneer Valley Life Science Institute, Baystate Medical Center, Springfield, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","unstructured":"Department of Health and Human Services National Institutes of Health and National Center for Chronic Disease Prevention and Health Promotion National Diabetes Statistics . Fact sheet. 2011."},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0366"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-s011"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.20.2579"},{"key":"e_1_3_5_6_2","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases . National diabetes statistics: 2007 and 2011 fact sheet. Bethesda MD: Department of Health and Human Services NIH 2008 and National Center for Chronic Disease Prevention and Health Promotion. 2011."},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1779"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.243386"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5302.964"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-013-1002-8"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20100429"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-1084"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.2337\/db06-1254"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.14740\/jem273w"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2013.08.004"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3422"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2016.03.407"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000046450.89986.50"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2010.006"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.245993"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.687376"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.1133"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0403954101"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-S011"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.5772\/66717"},{"key":"e_1_3_5_26_2","first-page":"299","article-title":"Gene transfer in endothelial dysfunction and hypertension","volume":"108","author":"Sen S","year":"2005","unstructured":"Sen S, Strappe PM, O'Brien T. Gene transfer in endothelial dysfunction and hypertension. Methods Mol Med. 2005;108:299\u2013314.","journal-title":"Methods Mol Med"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.458"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-015-0224-9"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.116.005146","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T10:21:34Z","timestamp":1715595694000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.116.005146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,5]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,4,5]]}},"alternative-id":["10.1161\/JAHA.116.005146"],"URL":"https:\/\/doi.org\/10.1161\/jaha.116.005146","relation":{},"ISSN":["2047-9980"],"issn-type":[{"type":"electronic","value":"2047-9980"}],"subject":[],"published":{"date-parts":[[2017,4,5]]},"assertion":[{"value":"2016-11-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-02-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e005146"}}