Inflammation-Mediated Regulation of MicroRNA Expression in Transplanted Pancreatic Islets

被引:34
作者
Bravo-Egana, Valia [1 ]
Rosero, Samuel [1 ]
Klein, Dagmar [1 ]
Jiang, Zhijie [2 ]
Vargas, Nancy [1 ]
Tsinoremas, Nicholas [2 ,3 ]
Doni, Marco [4 ,5 ]
Podetta, Michele [4 ,5 ]
Ricordi, Camillo [1 ,3 ,6 ,7 ,8 ,9 ]
Molano, R. Damaris [1 ]
Pileggi, Antonello [1 ,6 ,7 ,8 ,9 ]
Pastori, Ricardo L. [1 ,3 ]
机构
[1] Univ Miami, Diabetes Res Inst, Miami, FL USA
[2] Univ Miami, Ctr Computat Sci, Miami, FL USA
[3] Univ Miami, Leonard M Miller Sch Med, DeWitt Daughtry Dept Surg, Miami, FL USA
[4] Univ Miami, Leonard M Miller Sch Med, Dept Med, Miami, FL USA
[5] Fdn Policlin San Matteo, Ist Ricovero & Cura Carattere Sci, Inst Hepatopancreat Surg, Pavia, Italy
[6] Univ Pavia, Dept Surg Sci, Pavia, Italy
[7] Univ Miami, Leonard M Miller Sch Med, Dept Microbiol & Immunol, Miami, FL USA
[8] Univ Miami, Dept Med, Leonard M Miller Sch Med, Miami, FL USA
[9] Univ Miami, Dept Biomed Engn, Miami, FL USA
关键词
D O I
10.1155/2012/723614
中图分类号
R61 [外科手术学];
学科分类号
摘要
Nonspecific inflammation in the transplant microenvironment results in beta-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets. Islets exposed in vitro to proinflammatory cytokines and explanted syngeneic islet grafts were evaluated by miRNA arrays. A subset of 26 islet miRNAs was affected by inflammation both in vivo and in vitro. Induction of miRNAs was dependent on NF-kappa B, a pathway linked with cytokine-mediated islet cell death. RT-PCR confirmed expression of 8 miRNAs. The association between these miRNAs and mRNA target-predicting algorithms in genome-wide RNA studies of beta-cell inflammation identified 238 potential miRNA gene targets. Several genes were ontologically associated with regulation of insulin signaling and secretion, diabetes, and islet physiology. One of the most activated miRNAs was miR-21. Overexpression of miR-21 in insulin-secreting MIN6 cells downregulated endogenous expression of the tumor suppressor Pdcd4 and of Pclo, a Ca2+ sensor protein involved in insulin secretion. Bioinformatics identified both as potential targets. The integrated analysis of miRNA and mRNA expression profiles revealed potential targets that may identify molecular targets for therapeutic interventions.
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页数:15
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