Reduction of Cold Ischemic Injury with the Addition of Compound Glycyrrhizin in HTK Solution in a Mouse Heart Transplantation Model.

Cold ischemic injury in heart storage is an important issue pertaining to heart transplantation. This study aims to evaluate the addition of compound glycyrrhizin (CG) in histidine-tryptophan-ketoglutarate (HTK) solution on chronic isograft injury in comparison to traditional HTK solution.Hearts of mouse were stored for 8 h in 4°C cold preservation solution and then transplanted heterotopically into mouse. Five groups were evaluated: HTK, low dose of CG solution (LCG), medium dose of CG solution (MCG), high dose of CG solution (HCG), and hearts without cold ischemia (sham). Survival was assessed. Time to restoration of heartbeat and strength of the heartbeat was measured. Lactate dehydrogenase (LDH) and creatine kinase (CK) levels in the preservation solution were determined. The myocardial damage and interstitial fibrosis of transplanted hearts were evaluated. TGF-ß1 expression in the transplanted hearts was assessed.Addition of CG to HTK solution significantly attenuated cold ischemic injury during cold storage, as evidenced by the lower time to restoration of heartbeat, higher strength of the heartbeat, lower LDH, and CK leakage. After transplantation, hearts stored in HTK solution containing CG had decreased the myocardial damage and interstitial fibrosis, compared with those stored without CG. The percentage of TGF-ß1-positive cells and TGF-ß1 level in the transplanted hearts were also decreased when stored in CG-containing HTK solution.The addition of CG to HTK solution attenuates cold ischemic injury during cold storage.

Cold-inducible RNA binding protein agonist enhances the cardioprotective effect of UW solution during extended heart preservation.

In heart transplantation, time restriction is an unavoidable thorny problem during cardiac transport. Cold storage is an important organ preservation method in donor heart transport. Cold-inducible RNA binding protein (CIRBP) has been proven to play a protective role under cold stress. In this study, we investigated the role of CIRBP in hypothermic cardioprotection during heart preservation in UW solution and explored a new approach to extend the heart preservation time. Cirbp-knockout (Cirbp-/- ), Cirbp-transgenic (Cirbp-Tg), and wild-type rats were, respectively, randomized into two groups based on various heart preservation times (6 or 12-hour group) (n = 8 per group). After preservation in UW solution, all hearts were mounted on a Langendorff apparatus and underwent measurement of cardiac parameters, histological analysis, and molecular study. Within the 6-hour preservation group, no significant difference was found in cardiac functions and histological changes between different rat species. However, after 12 hours of preservation, Cirbp-/- rat hearts showed more apoptosis and worse cardiac function, but less apoptosis and better cardiac function were observed in Cirbp-Tg rat hearts. Furthermore, we found CIRBP-mediated cardiac ubiquinone (CoQ10 ) biosynthesis plays an important role in extending heart preservation, and ubiquinone biosynthesis protein COQ9 was an essential down-stream regulator during this process. Finally, we found that zr17-2, a CIRBP agonist, could enhance the expression of CIRBP, which further enhances the synthesis of CoQ10 and promotes scavenging of reactive oxygen species and ATP production to extend heart preservation. This study demonstrated that CIRBP-enhanced CoQ10 biosynthesis during hypothermic heart preservation and zr17-2-supplemented UW solution could be a promising approach to ameliorate heart damage and extend heart preservation during cardiac transport.

Addition of Berberine to Preservation Solution in an Animal Model of Ex Vivo Liver Transplant Preserves Mitochondrial Function and Bioenergetics from the Damage Induced by Ischemia/Reperfusion.

Liver transplantation is a therapeutic regimen to treat patients with non-malignant end-stage liver diseases and malignant tumors of hepatic origin. The ischemia/reperfusion (I/R) injury in liver transplantation is associated with disruption of mitochondrial function in the hepatic parenchyma. Several studies have been conducted in animal models to identify pharmacological therapeutic strategies to minimize the injury induced by the cold/warm I/R in liver transplantation. Most of these studies were conducted in unrealistic conditions without the potential to be translated to clinical usage. Berberine (BBR) is a pharmacological compound with a potential protective effect of the mitochondrial function in the context of I/R. For the future clinical application of these pharmacological strategies, it is essential that a close resemblance exists between the methodology used in the animals models and real life. In this study, we have demonstrated that the addition of BBR to the preservation solution in an I/R setting preserves mitochondrial function and bioenergetics, protecting the liver from the deleterious effects caused by I/R. As such, BBR has the potential to be used as a pharmacological therapeutic strategy.

Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats.

Chronic allograft nephropathy (CAN) is a common finding in kidney grafts with functional impairment. Prolonged hypothermic storage-induced ischemia-reperfusion injury is associated with the early onset of CAN. As the noble gas xenon is clinically used as an anesthetic and has renoprotective properties in a rodent model of ischemia-reperfusion injury, we studied whether early treatment with xenon could attenuate CAN associated with prolonged hypothermic storage. Exposure to xenon enhanced the expression of insulin growth factor-1 (IGF-1) and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. Xenon treatment before or after hypothermia-hypoxia decreased cell apoptosis and cell inflammation after reoxygenation. The xenon-induced HK-2 cell proliferation was abolished by blocking the IGF-1 receptor, mTOR, and HIF-1α individually. In the Fischer-to-Lewis rat allogeneic renal transplantation model, xenon exposure of donors before graft retrieval or recipients after engraftment enhanced tubular cell proliferation and decreased tubular cell death and cell inflammation associated with ischemia-reperfusion injury. Compared with control allografts, xenon treatment significantly suppressed T-cell infiltration and fibrosis, prevented the development of CAN, and improved renal function. Thus, xenon treatment promoted recovery from ischemia-reperfusion injury and reduced susceptibility to the subsequent development of CAN in allografts.