Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

Abstract

Pathophysiological alterations in the endothelial phenotype result in endothelial dysfunction. Flow cessation, occurring during organ procurement for transplantation, triggers the endothelial dysfunction characteristic of ischemia/reperfusion injury, partly due to a reduction in the expression of the vasoprotective transcription factor Kruppel-like Factor 2 (KLF2). We aimed at (1) characterizing the effects of flow cessation and cold storage on hepatic endothelial phenotype, and (2) ascertaining if the consequences of cold stasis on the hepatic endothelium can be pharmacologically modulated, improving liver graft function. Expression of KLF2 and its vasoprotective programs was determined in (i) hepatic endothelial cells (HEC) incubated under cold storage conditions with or without the KLF2-inducer simvastatin, and (ii) rat livers not cold stored or preserved in cold University of Wisconsin solution (UWS) supplemented with simvastatin or its vehicle. In addition, upon warm reperfusion hepatic vascular resistance, endothelial function, nitric oxide vasodilator pathway, apoptosis, inflammation, and liver injury were evaluated in not cold stored livers or livers preserved in cold UWS supplemented with simvastatin or vehicle. Expression of KLF2 and its vasoprotective programs decrease in HEC incubated under cold storage conditions. Cold-stored rat livers exhibit a time-dependent decrease in KLF2 and its target genes, liver injury, increased hepatic vascular resistance, and endothelial dysfunction. The addition of simvastatin to the storage solution, maintained KLF2-dependent vasoprotective programs, prevented liver damage, inflammation, and oxidative stress and improved endothelial dysfunction. Conclusion: Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation. (HEPATOLOGY 2012;55:921-930)

Enhancing organ pool by statins: Is this the future?

“…In that regard, recent 1111/j.1440-1746.2012.07160.x bs_bs_banner data demonstrated that liver grafts from healthy animals preserved in a commercially available cold storage solution supplemented with simvastatin exhibit reduced hepatocellular damage and improved microcirculatory status in comparison to grafts preserved in non-supplemented cold storage solution. 15 The excellent contribution of Ajamieh et al together with previous studies herein mentioned, strongly supports the concept that liver graft protection using a vasoprotective compound, such as simvastatin or atorvastatin, may represent an easy and inexpensive therapeutic option to increase organ pool and graft viability posttransplantation. Future studies will clarify the potential use of these drugs as cold storage supplements or as acute treatments prior to graft procurement in extended-criteria donors.…”

Hypothermic machine perfusion in liver transplantation

“…Machine perfusion may trigger endothelial protection because of upregulation of shear stress-sensitive protective genes (Fig. 3) [46]. Of note, however, a recent study failed to prove alteration of KLF2, in neither cold storage or machine perfusion compared with controls in porcine DCD kidneys, but showed increased activation of eNOS [49].…”

“…Liver endothelial cells are particularly vulnerable to ischemia/reperfusion injury and develop serious alterations during cold storage, such as retraction, cell body detachment, and apoptosis, whereas hepatocytes appear to be mostly unaffected [46,47]. During warm reperfusion, early sinusoidal endothelial cell (SEC) necrosis is followed by delayed hepatocyte apoptosis [47].…”

Clinical Perspective: Statins and the Liver—Harmful or Helpful?

“…A number of investigators have demonstrated potential mechanisms by which statins might reduce the development of HCC-either by inducing apoptosis in HCC cell lines [87,88] or via other means to modulate the growth of HCC cells [89,90]. Statins have also been shown to provide hepatoprotective properties in other situations [91][92][93].…”