Open AccessUse of p53‐Silenced Endothelial Progenitor Cells to Treat Ischemia in Diabetic Peripheral Vascular Disease
Author(s) -
Kundu Nabanita,
Domingues Cleyton C.,
Chou Cyril,
Ahmadi Neeki,
Houston Sara,
Jerry D. Joseph,
Sen Sabyasachi
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.116.005146
Subject(s) - medicine , streptozotocin , progenitor cell , diabetes mellitus , cd34 , endocrinology , transplantation , endothelial progenitor cell , vascular endothelial growth factor , stem cell , immunology , biology , microbiology and biotechnology , vegf receptors
Background Peripheral vascular disease is a major diabetes mellitus‐related 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‐ and p21‐silenced endothelial progenitor cells ( EPC s) were able to survive in hyperglycemic milieu, and whether transplantation of either p53 knockout (KO) or p21 KO or p53‐ and p21‐silenced EPC s could improve collateral vessel formation and blood flow in diabetic vaso‐occlusive peripheral vascular disease mouse models. Methods and Results We transplanted p53 and p21 KO mouse EPC s ( mEPC s) into streptozotocin–induced diabetic (type 1 diabetes mellitus model) C57 BL /6J and db/db (B6. BKS (D)‐Leprdb/J) (type 2 model) post–femoral artery occlusion. Similarly, Ad‐p53–silenced and Ad‐p21–silenced human EPC s ( CD 34+) cells were transplanted into streptozotocin‐induced diabetic NOD . CB 17‐Prkdcscid/J mice. We measured blood flow at 3, 7, and 10 days and hindlimb muscles were obtained postsacrifice for mRNA estimation and CD 31 staining. Enhanced blood flow was noted with delivery of p53 and p21 KO mEPC s in streptozotocin ‐induced diabetic C57 BL /6J mice. Similar results were obtained when human Ad‐p53sh EPC s( CD 34+) and Ad‐p21sh EPC s( CD 34+) were transplanted into streptozotocin‐induced nonobese diabetic severe combined immunodeficiency mice. Gene expression analysis of p53 and p21 KO EPC 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‐p53sh EPC s ( CD 34+)– and Ad‐p21sh EPC s ( CD 34+)–transplanted hindlimb muscles also showed increased expression of endothelial markers such as vascular endothelial growth factor A, noted primarily in the p53‐silenced EPC s group. However, such beneficial effect was not noted in the db/db type 2 diabetic mouse models. Conclusions Transient silencing of p53 using adenoviral vector in EPC s may have a therapeutic role in diabetic peripheral vascular disease.