CORMs protect endothelial cells during cold preservation, resulting in inhibition of intimal hyperplasia after aorta transplantation in rats

Abstract

Summary Allograft vasculopathy is the leading cause for chronic transplant loss. We investigated if the addition of carbon monoxide releasing molecules (CORMs) to the preservation solution would protect the endothelium from cold preservation injury in an aortic transplantation model. In particular, we tested if CORM preserve vascular functioning and limit neo‐intima formation following cold preservation (Cp). Abdominal aortas from Lewis or Fisher rats were subjected to Cp in University of Wisconsin (UW) solution to which 50 μm of CORM‐3 was added or not. Hereafter, whole mount staining, acetylcholine mediated vasorelaxation (AMV) and aortic transplantation was performed. In vitro CORM‐3 protected human umbilical vein endothelial cells from Cp injury and prevented denudation and intercellular gap formation in aortic grafts. Cp resulted in loss of AMV of aorta segments. By contrast, AMV was preserved after the addition of CORM‐3 during Cp. Two months after transplantation Cp of aorta grafts resulted in an increased adventitial remodelling and neo‐intima formation. This was significantly blunted by CORM‐3 in syngeneic recipients. Our study demonstrates that addition of CORM‐3 to UW solution prevents endothelial damage, thereby maintaining vascular function directly after cold preservation. Hence, our findings might offer a novel strategy to prevent vascular damage during CP.

Different design of enzyme-triggered CO-releasing molecules (ET-CORMs) reveals quantitative differences in biological activities in terms of toxicity and inflammation

“…Pre-clinical studies with the most widely used CORMs, i.e. CORM2A and CORM-3, have clearly demonstrated their therapeutic efficacy in settings of fibrosis [35], inflammation [32,36–38], vascular dysfunction [35,39] and oxidative damage [39]. Yet it should be underscored that these CORMs predominantly deliver CO to cells and tissue via passive diffusion once CO is released rather than a direct intracellularly delivery of CO.…”

The immunomodulatory role of carbon monoxide during transplantation

“…Similar results were observed in CORM-3-treated hepatic cold preservation [188]. In a rat model, CORM-3 improved aorta graft adventitial remodeling and neo-intima formation [189]. The combination of CO and biliverdin treatment for heart and kidney grafts resulted in protection against ischemia-reperfusion injury [190].…”

Enhancement of bradykinin-induced relaxation by focal brain ischemia in the rat middle cerebral artery: Receptor expression upregulation and activation of multiple pathways

“…Tension was measured by force transducers (F10, coupled to TAM-A amplifiers, both from Hugo Sachs, March-Hugstetten, Germany). The signals from the force detection systems were fed into a computer and continuously recorded using a purpose-built program based on LabView (Munich, Germany) as described previously [ 22 ].…”