Flow cessation triggers endothelial dysfunction during organ cold storage conditions: Strategies for pharmacologic intervention

Jorge Gracia-Sancho, Guadalupe Villarreal, Yuzhi Zhang, Jessica X. Yu, Yao Liu, Stefan G. Tullius, Guillermo García-Cardeña

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)142-149
Number of pages8
JournalTransplantation
Volume90
Issue number2
DOIs
StatePublished - Jul 27 2010
Externally publishedYes

Keywords

  • Cold storage
  • Endothelium
  • KLF2
  • Shear stress
  • Statins

ASJC Scopus subject areas

  • Transplantation

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