Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention.
BACKGROUND
Vascular pathologies constitute a major cause of graft rejection after organ transplantation. Recent studies have documented an improvement in transplant outcome when organs are preserved through pulsatile perfusion; however, the underlying mechanisms of these observations are poorly characterized. We hypothesized that the temporary absence of flow occurring in the context of organ cold storage conditions disrupts endothelial vasoprotective programs, and that this consequence of stasis may be a target for pharmacological modulation.


METHODS
The expression of the transcription factor Kruppel-like factor 2 (KLF2) and its vasoprotective target genes were assessed during cold storage conditions in cultured human endothelial cells and murine aortic segments. In addition, we evaluated the effect of simvastatin used as a supplement in a cold preservation solution on the expression of vasoprotective genes, and on endothelial activation and apoptosis.


RESULTS
The expression of endothelial KLF2 and its vasoprotective transcriptional targets were rapidly lost during cold preservation in vitro and ex vivo. Importantly, simvastatin treatment blocked the decay of KLF2, sustaining a vasoprotective phenotype, and preventing endothelial activation and apoptosis.


CONCLUSIONS
Flow stasis leads to acute endothelial dysfunction and apoptosis in the context of cold storage conditions. Supplementation of organ preservation solutions with pharmacologic agents that restore endothelial vasoprotective programs, by upregulating KLF2, may represent a significant advancement of current organ preservation techniques.
Gracia-Sancho
Jorge
J
Department of Pathology, Laboratory for Systems Biology, Center for Excellence in Vascular Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Villarreal
Guadalupe
G
Zhang
Yuzhi
Y
Yu
Jessica X
JX
Liu
Yao
Y
Tullius
Stefan G
SG
García-Cardeña
Guillermo
G
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion; D018929:Cell Culture Techniques / Q000379:methods; D015925:Cryopreservation / Q000379:methods*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D020868:Gene Silencing; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009926:Organ Preservation / Q000379:methods* / Q000592:standards; D019188:Organ Preservation Solutions / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014471:Umbilical Veins; D015854:Up-Regulation
C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D019188:Organ Preservation Solutions; D034741:RNA, Small Interfering; D019821:Simvastatin