Reduction of cold ischemia–reperfusion injury by graft-expressing clusterin in heart transplantation

Li, Shuyuan; Guan, Qiunong; Chen, Zhishui; Gleave, Martin; Nguan, Christopher; Du, Caigan

doi:10.1016/j.healun.2011.03.007

Cited by 22 publications

(24 citation statements)

References 27 publications

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“…Clusterin expression renders donor hearts resistance to cold I/R injury in transplantation, suggesting that upregulation of clusterin expression in donor hearts may have the potential to protect heart grafts from cold I/R injury [24,25]. In this study, we found that the expression of pro-inflammatory cytokines (IL-1β and TNF-α) was impeded by hr clusterin treatment in a cold I/R model.…”

Section: Discussionmentioning

confidence: 57%

Clusterin Reduces Cold Ischemia-Reperfusion Injury in Heart Transplantation Through Regulation of NF-kB Signaling and Bax/Bcl-xL Expression

Liu

Zhang

Hao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ischemia-reperfusion (I/R) injury is an unavoidable event occurring during heart transplantation and is a key factor in graft failure and the long-term survival rate of recipients. Therefore, there is an urgent need for the development of new therapies to prevent I/R injury. Clusterin is a hetero-dimeric glycoprotein with an antiapoptotic function. In this study, we investigated whether clusterin was cardioprotective in heart transplantation against I/R injury using an in vivo rat model and an in vitro cell culture system, and examined the underlying mechanisms of I/R injury. Methods: Heart grafts from wild-type C57BL/6 mice were preserved in UW solution (control) or UW solution containing recombinant human apolipoprotein-J (hr clusterin) for 24 h. The preserved hearts were implanted into recipient mice of the same strain as the donors for 72 h, and the heart grafts were then taken for histopathological and gene expression analyses. An in vitro ischemia reperfusion model using H9C2 cells or H9C2/clusterin cDNA cells was constructed. The expression of clusterin, p65, Bax, Bcl-xL, IL-1β, and TNF-α protein and mRNA in heart tissue and H9C2 cells was detected by western blot, reverse transcription-polymerase chain reaction (RT-PCR), and quantitative RT-PCR assays; IL-1β and TNF-α protein was detected by enzyme-linked immunosorbent assays; NF-kB activity was detected by an electrophoretic mobility shift assay; cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometric analyses. Results: Cold I/R caused severe morphologic myocardial injury to heart grafts from wild-type C57BL/6 mice, whereas grafts from hr clusterin preservation showed less damage, as demonstrated by decreased cell apoptosis/death, decreased neutrophil infiltration, and the preservation of the normal structure of the heart. Clusterin reduced the expression of p65, pre-inflammatory IL-1β, and TNF-α, and the pro-apoptotic gene Bax, while it enhanced

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Section: Discussionmentioning

confidence: 57%

Clusterin Reduces Cold Ischemia-Reperfusion Injury in Heart Transplantation Through Regulation of NF-kB Signaling and Bax/Bcl-xL Expression

Liu

Zhang

Hao

et al. 2018

Cell Physiol Biochem

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“…As we know, donor hearts for heart transplantation underwent cold ischemia (organ-preserving cold storage interval) and extracorporeal circulation before the heart completely restored function in recipients. Necrosis and apoptosis of cardiomyocytes occurred after ischemia in donor hearts [15,16,24-26]. Exosomes or microvesicles containing miRNAs will be released from cardiomyocytes into blood [27].…”

Section: Discussionmentioning

confidence: 99%

“…The donor heart undergoes cold ischemia and ischemia-reperfusion injury during extracorporeal circulation, both of which induce necrosis and apoptosis of cardiomyocytes in donor heart and subsequent myocardial injury early after transplantation [15,16]. Review of the International Society for Heart and Lung Transplantation (ISHLT) Registry has shown that donor-related variables, particularly duration of myocardial ischemia, continue to emerge as an independent risk factor for early and late survival and cardiac allograft vasculopathy [17].…”

Section: Introductionmentioning

confidence: 99%

Circulating miRNAs reflect early myocardial injury and recovery after heart transplantation

Wang

Nie

Zhao

et al. 2013

J Cardiothorac Surg

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BackgroundMicroRNAs (miRNAs) are short, single-stranded and non-coding RNAs, freely circulating in human plasma and correlating with vary pathologies. In this study, we monitored early myocardial injury and recovery after heart transplantation by detecting levels of circulating muscle-specific miR-133a, miR-133b and miR-208a.Methods7 consecutive patients underwent heart transplantation in Fuwai hospital and 14 healthy controls were included in our study. Peripheral vein blood was drawn from patients on the day just after transplantation (day 0), the 1st, 2nd, 3rd, 7th and 14th day after transplantation respectively. Serum from peripheral blood was obtained for cardiac troponin I (cTnI) measurement. Plasma was centrifuged from peripheral blood for measuring miR-133a, miR-133b and miR-208a by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The plasma concentration of miRNAs were calculated by absolute quantification method. The sensitivity and specificity of circulating miRNAs were revealed by receiver operating characteristic curve (ROC) analysis. Correlations between miRNAs and cTnI / perioperative parameters were analyzed.ResultsSimilar to cTnI, miR-133a, miR-133b and miR-208a all showed dynamic changes from high to low levels early after operation. The Sensitivity and specificity of miRNAs were: miR-133a (85.7%,100%), miR-208a (100%,100%), and miR-133b (90%,100%). Correlations between miRNAs and cTnI were statistically significant (p < 0.05), especially for miR-133b (R2 = 0.813, p < 0.001). MiR-133b from Day 0-Day 2 (r > 0.98, p < 0.01), and cTnI from Day 1- Day 3 (r > 0.86, p < 0.05) had strong correlations with bypass time, particularly parallel bypass time. Obviously, miR-133b had a better correlation than cTnI. Circulating miR-133b correlated well with parameters of heart function such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and inotrope support, while cTnI only correlated with 3 of the 4 parameters mentioned above. MiR-133b also had strong correlations with ventilation time (r > 0.99, p < 0.001) and length of ICU stay (r > 0.92, p < 0.05), both of which reflected the recovery after operation. The correlation coefficients of miR-133b were also higher than that of cTnI.ConclusionsThe dynamic change in circulating muscle-specific miRNAs, especially miR-133b can reflect early myocardial injury after heart transplantation. And miR-133b may have advantages over cTnI in forecasting graft dysfunction and recovery of patients after operation.

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“…Clusterin confers a protective function in mouse models of tissue injury 5 . Moreover, obesity and insulin resistance are important CVD risk factors 100 . These observations suggest that depletion of clusterin in HDL might impair its cardioprotective function.…”

Section: Other Causes Of Dysfunctional Hdlmentioning

confidence: 99%

Dysfunctional HDL and atherosclerotic cardiovascular disease

et al. 2015

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High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

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Reduction of cold ischemia–reperfusion injury by graft-expressing clusterin in heart transplantation

Cited by 22 publications

References 27 publications

Clusterin Reduces Cold Ischemia-Reperfusion Injury in Heart Transplantation Through Regulation of NF-kB Signaling and Bax/Bcl-xL Expression

Clusterin Reduces Cold Ischemia-Reperfusion Injury in Heart Transplantation Through Regulation of NF-kB Signaling and Bax/Bcl-xL Expression

Circulating miRNAs reflect early myocardial injury and recovery after heart transplantation

Dysfunctional HDL and atherosclerotic cardiovascular disease

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