scholarly journals Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury

2021 ◽  
Vol 22 (20) ◽  
pp. 11038
Author(s):  
Adnan Qamar ◽  
Jianqi Zhao ◽  
Laura Xu ◽  
Patrick McLeod ◽  
Xuyan Huang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Transplant Rejection ◽  
Microvascular Endothelial Cell ◽  
Cardiac Transplant ◽  
Cyclophilin D ◽  
Iri Model ◽  
Organ Rejection

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival.

scholarly journals Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation

2005 ◽  
Vol 25 (7) ◽  
pp. 868-877 ◽  
Author(s):  
Yunhong Zhang ◽  
Xiaochun Zhang ◽  
Tae S Park ◽  
Jeffrey M Gidday
Keyword(s):  
Endothelial Cell ◽  
Cell Viability ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion ◽  
Total Duration ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Microvascular Endothelial Cell ◽  
Parp Activation ◽  
Cerebral Endothelial Cell ◽  
Parp 1

Cerebral ischemia-reperfusion leads to vascular dysfunction characterized by endothelial cell injury or death. In the present study, we used an in vitro model to elucidate mechanisms of human brain microvascular endothelial cell (HBMEC) injury after episodic ischemia-reperfusion. Near-confluent HBMEC cultures were exposed to intermittent hypoxia-reoxygenation (HX/RO) and, at different recovery time points, cell viability was assessed by the MTT assay, apoptotic death by fluorescence microscopy of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL)-positive cells, and nuclear translocation of apoptosis-inducing factor (AIF) and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) by immunoblotting of subcellular fractions. Reductions in HBMEC viability were proportional to the number of HX/RO cycles, and not the total duration of hypoxia. Using four cycles of 1-h HX with 1 h of intervening normoxic RO, cell viability was reduced 30% to 40% between 12 and 48 h. Treatment with the PARP-1 inhibitors 3-aminobenzamide or 4-amino-1,8-naphthalimide during the insult improved HBMEC viability at 24 h after insult, and resulted in dose-dependent reductions in TUNEL-positivity at 16 h after insult, but not if these treatments were delayed by 4 h. HX/RO-induced increases in nuclear AIF translocation, as well as PARP-1 cleavage, were also reduced dose-dependently at 4 h after insult by the inhibitors. The caspase inhibitor z-VAD-fmk blocked PARP-1 cleavage, but did not affect AIF translocation and was only modestly cytoprotective. These findings indicate that PARP-1 activation and a PARP-1-dependent, caspase-independent, nuclear translocation of AIF contribute to apoptotic cerebral endothelial cell death after ischemia-reperfusion, underscoring the potential for ischemic microvascular protection by inhibiting PARP activation or preventing AIF translocation.

scholarly journals LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽  
2021 ◽  
Author(s):  
Jiaying Zhu ◽  
Zhu Zhu ◽  
Yipin Ren ◽  
Yukang Dong ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Mice Model ◽  
Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

scholarly journals Noninvasive Imaging of Activated Complement in Ischemia-Reperfusion Injury Post-Cardiac Transplant

2015 ◽  
Vol 15 (9) ◽  
pp. 2483-2490 ◽  
Author(s):  
E. Sharif-Paghaleh ◽  
M. L. Yap ◽  
L. L. Meader ◽  
K. Chuamsaamarkkee ◽  
F. Kampmeier ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Noninvasive Imaging ◽  
Cardiac Transplant

Abstract MP58: Tissue And Sex Specific Effects Of Gstm1 Deletion In Mouse Models

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yves Wang ◽  
Nhu Nguyen ◽  
Keith Nehrke ◽  
Paul S Brookes ◽  
Thu H Le
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Properties ◽  
Iri Model ◽  
Increased Risk ◽  
Study Gene Expression

The glutathione S-transferase ( Gst ) gene family encodes antioxidant enzymes. In humans, a common null allele deletion variant of GST μ-1 ( GSTM1 ) is highly prevalent across populations and is associated with increased risk and progression of various diseases. Using a Gstm1 knockout (KO) mouse model, we previously showed that KO mice with angiotensin II-induced hypertension (HTN) have increased kidney injury compared to wild-type (WT) controls, mediated by elevated oxidative stress. In the same mouse model, we have recently reported that in a Langendorff-perfused cardiac ischemia-reperfusion injury (IRI) model, where damage is also mediated by oxidative stress, male KO hearts are protected while females are not. Here, we investigated the molecular mechanisms for this difference in male hearts. WT and KO mice of both sexes were studied at 12-20 weeks of age. Hearts were snap frozen at baseline and after 25 min of global ischemia, and kidneys were collected at baseline and 4 weeks following HTN induction. A panel of 18 Gst genes were probed by qPCR from baseline hearts and kidneys of both sexes. Global metabolites were assayed using Metabolon, Inc. from hearts of both sexes and kidneys of males, at both baseline and diseased states. Analysis by qPCR (n = 3/group) showed that male, but not female, KO hearts had upregulation of other Gst s. In contrast, no significant differences between were found in male kidneys. Metabolomics (n = 6/group) detected 695 metabolites in hearts and 926 in kidneys. There were increases in several metabolites in KO vs. WT hearts including those with antioxidant properties. Notably, increases in carnosine and anserine were observed in KO male hearts but not in female hearts, while that of other antioxidant-related metabolites were observed in hearts of both sexes, but not in kidneys. HTN induced significant increases in metabolites in KO vs. WT kidneys in the pathways related to and linking methionine, cysteine, and glutathione, which were not observed in hearts. In this study, gene expression and metabolites suggest that the mechanisms compensating for the loss of GSTM1 are both tissue and sex specific. The resulting differences in antioxidant enzymes and metabolites may explain the unexpected protection for male Gstm1 KO hearts in IRI.

scholarly journals Endothelial cell-derived exosomes protect SH-SY5Y nerve cells against ischemia/reperfusion injury

2017 ◽  
Vol 40 (4) ◽  
pp. 1201-1209 ◽  
Author(s):  
Bing Xiao ◽  
Yi Chai ◽  
Shigang Lv ◽  
Minhua Ye ◽  
Miaojing Wu ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nerve Cells

scholarly journals Markers of endothelial dysfunction after cardiac surgery: Soluble forms of vascular-1 and intercellular-1 adhesion molecules

Medicina ◽  
2009 ◽  
Vol 45 (6) ◽  
pp. 434 ◽  
Author(s):  
Mindaugas Balčiūnas ◽  
Loreta Bagdonaitė ◽  
Robertas Samalavičius ◽  
Alis Baublys
Keyword(s):  
Cardiac Surgery ◽  
Endothelial Dysfunction ◽  
Reperfusion Injury ◽  
Adhesion Molecules ◽  
Heart Surgery ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Transplant Rejection ◽  
Vascular Wall ◽  
Tissue Ischemia

Endothelium forms an inner layer of vascular wall. It plays an important role in inflammatory process, regulation of vascular tone, and synthesis of thromboregulatory substances. Leukocyte and endothelium interactions during inflammation are regulated by different families of adhesion molecules. Increased levels of soluble forms of adhesion molecules have been detected in the circulating blood in conditions such as autoimmune diseases, transplant rejection, ischemia-reperfusion injury in addition to neutrophil- and endothelial membrane-bound forms reflecting the level of endothelial dysfunction. It is known that endothelial dysfunction is a risk factor for ischemic events such as stroke, myocardial infarction, unstable angina pectoris, ventricle fibrillation, necessity of revascularisation procedures, and death from cardiovascular reasons. Clinical studies showed that cardiac surgery has an impact on vascular endothelial function as well. The amount of endotheliumderived soluble forms of vascular-1 and intercellular-1 adhesion molecules increases after cardiopulmonary bypass suggesting endothelial dysfunction. However, further investigations are needed to be done to support the evidence that endothelial dysfunction proceeding heart surgery is one of the reasons of tissue ischemia-reperfusion injury.

Abstract 4364: Gender-Specific Regulation of Ncx in Human Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Constance E Mash ◽  
Wendy E Sweet ◽  
Christine S Moravec
Keyword(s):  
Human Heart ◽  
Ischemia Reperfusion Injury ◽  
Calcium Influx ◽  
Ischemia Reperfusion ◽  
Cardiac Transplant ◽  
Heart Cells ◽  
Male Population ◽  
Human Heart Failure ◽  
Male And Female ◽  
Males And Females

We and others have previously reported increased protein levels of the sarcolemmal sodium-calcium exchanger (NCX) in failing (F) vs non-failing (NF) human hearts. In the non-failing cardiomyocyte, NCX transports calcium out of the cell following contraction, in an amount roughly equal to that which enters the cell through L type calcium channels upon depolarization. In the face of decreased sarcoplasmic reticulum calcium ATPase (SERCA) function in the F human heart, up-regulation of NCX is thought to be a compensatory change, helping to prevent calcium overload. It has also been demonstrated that NCX may work in reverse mode in F heart cells, providing for increased calcium influx during the action potential plateau. Recent studies have suggested that over-expression of NCX has different functional consequences in male and female animal hearts during metabolic inhibition as well as ischemia/reperfusion injury, yet studies demonstrating up-regulation of NCX in F human hearts have largely pooled male and female hearts. We have measured NCX and SERCA in a population of male and female F and NF human hearts. Nine patients were studied per group. F hearts were explanted from cardiac transplant recipients with diagnosis of dilated cardiomyopathy and NF hearts from unmatched organ donors. Immunoblotting was used to quantify NCX and SERCA, normalized to actin. NCX was increased in both male and female F hearts as compared to NF hearts, but the increase was proportionately greater in the male population (Normalized values: Male F 3.30 vs NF 1.0; Female F 2.60 vs NF 1.0). Comparison of NF hearts from males and females, however, demonstrated that levels of NCX protein are consistently higher in female than male hearts (Female NF 2.18 vs Male 1.0). SERCA protein was decreased in both male and female F hearts to equal degrees as compared to both groups of NF hearts (Male F 0.65 vs NF 1.0; Female F 0.65 vs NF 1.0), with no difference in NF levels between males and females (female NF 1.1 vs Male 1.0). These data suggest that NCX is regulated differently in male and female F human hearts, which may play a role in the ability of the heart to preserve adequate calcium cycling during cardiac dysfunction.

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