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Thorac Cardiovasc Surg 2019; 67(06): 503-512
DOI: 10.1055/s-0038-1673633
Original Basic Science
Georg Thieme Verlag KG Stuttgart · New York

Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model

Rawa Arif   *
1   Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
,
Maximilian Franz   *
1   Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
,
Anca Remes
2   Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Marcin Zaradzki
1   Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
,
Markus Hecker
2   Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
,
Matthias Karck
1   Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
,
Oliver J. Müller
3   Department of Internal Medicine III, University Hospital Kiel, Kiel, Germany
,
Klaus Kallenbach
4   Department of Cardiac Surgery, INCCI HaerzZenter, Luxembourg, Luxembourg
,
Andreas H. Wagner
2   Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

08 May 2018

23 August 2018

Publication Date:
23 October 2018 (online)

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Abstract

Background Transplant vasculopathy (TV) is the main limiting factor for long-term graft survival characterized by fibrosis, myofibroblast, and smooth muscle cell (SMC) proliferation. Decoy oligodeoxynucleotide (dODN) against the transcription factor activator protein-1 (AP-1) might interfere with the expression of AV-related genes that govern neointima formation.

Methods Aortic allografts from DBA/2 mice were incubated with control buffer, consensus, or mutated control AP-1 dODN and were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight [BW]) was administered daily. Explantation and histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography.

Results Intima-to-media (I/M) ratio and neointima formation were significantly reduced in the consensus AP-1 dODN treatment group by 37% (p < 0.05) and 67% (p < 0.01), respectively. SMC α-actin-2 staining and macrophage marker expression revealed a marked reduction in the neointima. I/M ratio was found to correlate with the number of tissue macrophages (p < 0.05). MMP and fibrosis marker expression were not significantly altered.

Conclusion Intraoperative AP-1dODN utilization might be a strategy to preserve graft function after transplantation.

Keywords

decoy oligodeoxynucleotide - transplant vasculopathy - activator protein-1

* Both authors contributed equally.


Author Contributions

Rawa Arif participated in the design of the experimental procedures, in performing animal surgeries, and in the writing of the manuscript. He contributed to the conceptualization of the overall research goals and writing the manuscript. He designed the methodology, was involved in performing experiments and in acquisition of financial support for the project, and was responsible for management and coordination of research activities. Maximilian Franz participated in performing animal surgeries and experimental procedures, in evaluation of the data, and in the writing of the manuscript. He also performed the largest part of experiments, applied analysis and statistical technology to analyze the study data, and was involved in writing the manuscript. Anca Remes and Marcin Zaradzki participated in performing histological procedures and analyses. Markus Hecker, Oliver J. Müller, and Matthias Karck participated in writing the manuscript and provided administrative and supervisory support. Klaus Kallenbach contributed to the design of the study, participated in writing the manuscript, and provided administrative and supervisory support. Andreas H. Wagner planned and supervised the study and wrote the manuscript.


 

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