Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury

Uchida, Yasushi; Tamaki, Tohru; Tanaka, Mitsuko; Kubo, Takashi; Tsuchihashi, Seiichiro; Takahashi, Tsuyoshi; Kawamura, Akio; Kakita, Akira

doi:10.1007/s00147-003-0550-1

Cited by 11 publications

(11 citation statements)

References 36 publications

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“…SnPP treatment has been shown to inhibit enzyme activity, resulting in an induction of protein expression in rat liver allografts. 26 Similar to our data, SnPP treatment has been shown to reduce HO-1 enzyme activity and expression in rat basophil leukemia cells. 27 Although our data demonstrate elevated plasma HO-1 levels in response to rosiglitazone treatment, the exact source of this HO-1 is yet unknown, and the differential expression and regulation of HO-1 requires further investigation.…”

Section: Discussionsupporting

confidence: 91%

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

et al. 2011

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Abstract-Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-␥ (PPAR-␥) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-␥ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-␥ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-␥ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tinprotoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-␥ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia. (Hypertension. 2011;58:280-286.) • Online Data SupplementKey Words: peroxisome proliferator-activated receptor-␥ Ⅲ preeclampsia Ⅲ reduced uterine perfusion pressure Ⅲ hypertension Ⅲ heme oxygenase 1 Ⅲ vascular dysfunction P reeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide, causing Ϸ15% of all direct maternal deaths and mediating a 5-fold increase in perinatal mortality. 1 Although the underlying etiology of preeclampsia is poorly understood, it is characterized by a relatively hypoperfused placenta, which stimulates the maternal response manifesting as hypertension, vascular dysfunction, alterations in platelet aggregation, and a pro-oxidant state. 2 There is currently no effective pharmacological intervention available for the treatment of preeclampsia, and, consequently, pregnancies are often delivered preterm for maternal benefit, imposing the challenges of iatrogenic prematurity on the fetus. 3 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of a number of genes involved in cell differentiation and proliferation. 4 PPAR-␥ plays a predominant role in normal vascular function 5 and in the differ...

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Section: Discussionsupporting

confidence: 91%

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

et al. 2011

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“…Thus, HO-1 overexpression by pharmacological means or via genetic engineering has been shown to exert potent cytoprotective effects in hepatic IRI transplant models, where both proinflammatory and apoptotic responses remain profoundly diminished in HO-1-overexpressing liver transplants (9 -11). In contrast, the lack or inhibition of HO-1 which generally accelerates host inflammatory responses, as shown in HO-1-deficient mice (12) as well as in HO-1 deficiency reported in humans (13), has yielded contrasting evidence in the liver IRI (11,14).…”

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confidence: 99%

Basal Rather Than Induced Heme Oxygenase-1 Levels Are Crucial in the Antioxidant Cytoprotection

Tsuchihashi

Livhits

Zhai

et al. 2006

The Journal of Immunology

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Heme oxygenase-1 (HO-1) overexpression protects against tissue injury in many inflammatory processes, including ischemia/reperfusion injury (IRI). This study evaluated whether genetically decreased HO-1 levels affected susceptibility to liver IRI. Partial warm ischemia was produced in hepatic lobes for 90 min followed by 6 h of reperfusion in heterozygous HO-1 knockout (HO-1+/−) and HO-1+/+ wild-type (WT) mice. HO-1+/− mice demonstrated reduced HO-1 mRNA/protein levels at baseline and postreperfusion. This corresponded with increased hepatocellular damage in HO-1+/− mice, compared with WT. HO-1+/− mice revealed enhanced neutrophil infiltration and proinflammatory cytokine (TNF-α, IL-6, and IFN-γ) induction, as well as an increase of intrahepatic apoptotic TUNEL+ cells with enhanced expression of proapoptotic genes (Bax/cleaved caspase-3). We used cobalt protoporphyrin (CoPP) treatment to evaluate the effect of increased baseline HO-1 levels in both WT and HO-1+/− mice. CoPP treatment increased HO-1 expression in both animal groups, which correlated with a lower degree of hepatic damage. However, HO-1 mRNA/protein levels were still lower in HO-1+/− mice, which failed to achieve the degree of antioxidant hepatoprotection seen in CoPP-treated WT. Although the baseline and postreperfusion HO-1 levels correlated with the degree of protection, the HO-1 fold induction correlated instead with the degree of damage. Thus, basal HO-1 levels are more critical than the ability to up-regulate HO-1 in response to the IRI and may also predict the success of pharmacologically induced cytoprotection. This model provides an opportunity to further our understanding of HO-1 in stress defense mechanisms and design new regimens to prevent IRI.

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“…We have previously reported that prior induction of HO-1 gene expression with a concomitant increased activity by hemin in donor livers could be associated with partial cytoprotection against hepatic cold I/R injury. Interestingly, SnPP, a potent competitive inhibitor of HO enzyme activity, did not eliminate the effects of hemin but rather conferred more beneficial effects, as indicated by histology and animal survival [35]. Since SnPP reduced HO enzyme activity below the baseline level, it was unlikely that the end products of heme degradation, including bilirubin and carbon monoxide, could be directly linked to cytoprotection against hepatic I/R injury.…”

Section: Discussionmentioning

confidence: 99%

“…After centrifugation at 10,000 g for 15 min, the amount of bilirubin was determined according to a method described previously [39]. As a positive control we used 60 pmol/kg of ferri-protoporphyrin IX chloride (Hemin, Sigma Chemical, St. Louis, Mo., USA), a potent inducer of HO-1 activity [35]. Enzyme activity was expressed as picomoles of bilirubin per milligram of tissue protein generated for 30 min.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury

et al. 2003

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Heme oxygenase-1 (HO-1) has been shown to increase cellular resistance against oxidative injury, but the functional significance of this is currently obscure. We investigated the protective role of HO-1, induced by tin-protoporphyrin IX (SnPP), in attenuating liver transplantation injury. Lewis rats were intraperitoneally treated with saline as control, 50 pmol/kg of SnPP, or 2 mg/kg of cycloheximide (CHX) before SnPP injection. Gene expression of HO-1 was induced after either treatment with SnPP-or CHX + SnPP instead of saline, whereas HO-1 protein synthesis was enhanced in Kupfferlike dendritic cells of the SnPPtreated group. Following reperfusion of liver grafts preserved for 30 h, there were fewer intercellular adhesion molecule-1 -positive cells in SnPP-treated livers, significantly reduced numbers of dead cells, and enhanced graft viability. The present data suggest that increased synthesis of HO-1 protein by SnPP pre-conditioning is linked to the improved liver graft viability through inhibition of inflammatory adhesion molecules.Keywords Heme oxygenase-1 . Cold ischemia and reperfusion injury . Tin-protoporphyrin . Intercellular adhesion molecule-1 Despite the success of liver transplantation, ischemia and reperfusion (I/R) injury remains a serious problem that affects the outcome in the treatment of patients following hepatectomy and liver transplantation. Although there has been significant effort to identify the mechanisms of reperfusion injury following extended hepatic ischemia, there is no clinically proven means except for the avoidance of warm ischemia and the reduction of cold preservation time. Donor pre-conditioning by ischemic or pharmacological maneuvers has been recently shown to attenuate post-ischemic reperfusion injury in cardiac, renal, and hepatic animal models [15,17,30, 341. The underlying mechanisms may involve the generation of vaso-active molecules such as nitric oxide and adenosine or the expression of stressresponse genes including superoxide dismutase and heat shock proteins (HSPs) [20, 23, 26, 381.

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Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury

Cited by 11 publications

References 36 publications

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

Basal Rather Than Induced Heme Oxygenase-1 Levels Are Crucial in the Antioxidant Cytoprotection

Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury

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