title: RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection.
abstract: Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: L N L
authors.initials: LN
authors.lastname: Van Aelst
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, Maastricht, the Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Summer
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: W
authors.initials: W
authors.lastname: Heggermont
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: De Vusser
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.|Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, Maastricht, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Carai
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Naesens
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Cleemput
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Van de Werf
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Vanhaecke
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Thum
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Waer
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.|Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, Maastricht, the Netherlands.
authors.forename: A-P
authors.initials: AP
authors.lastname: Papageorgiou
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, Maastricht, the Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Schroen
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.|Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, Maastricht, the Netherlands.|ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Heymans
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D016030:Kidney Transplantation / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012333:RNA, Messenger
keywords: basic (laboratory) research/science; heart (allograft) function/dysfunction; heart transplantation/cardiology; microarray/gene array; molecular biology: mRNA/mRNA expression; molecular biology: micro RNA; rejection: acute