Activated regulatory T-cells attenuate myocardial ischaemia/reperfusion injury through a CD39-dependent mechanism

2015 ◽  
Vol 128 (10) ◽  
pp. 679-693 ◽  
Author(s):  
Ni Xia ◽  
Jiao Jiao ◽  
Ting-Ting Tang ◽  
Bing-Jie Lv ◽  
Yu-Zhi Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Adoptive Transfer ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Treg Population ◽  
Dependent Mechanism

Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using ‘depletion of regulatory T-cell’ (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)–GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF)-β1 inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4+CD25+CD127low Tregs and a relative increase in CD39+ cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy.

The effect of relaxin on myocardial ischaemia-reperfusion injury and histamine release in vitro and in vivo

1996 ◽  
Vol 45 (S1) ◽  
pp. S27-S28 ◽  
Author(s):  
E. Masini ◽  
D. Salvemini ◽  
L. Mugnai ◽  
M. G. Bello ◽  
D. Bani ◽  
...  
Keyword(s):  
Histamine Release ◽  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Release In Vitro

scholarly journals miRNA-146a Mimic Inhibits NOX4/P38 Signalling to Ameliorate Mouse Myocardial Ischaemia Reperfusion (I/R) Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Lili Xiao ◽  
Yulei Gu ◽  
Gaofei Ren ◽  
Linlin Chen ◽  
Liming Liu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Underlying Mechanism ◽  
Neonatal Rat ◽  
Ischaemia Reperfusion Injury ◽  
Rat Cardiomyocytes ◽  
Ischaemia Reperfusion ◽  
Ros Accumulation

Evidence suggests that miR-146a is implicated in the pathogenesis of cardiovascular diseases; however, the role of miR-146a in myocardial ischaemia reperfusion (I/R) injury is unclear. The aim of this study was to explore the functional role of miR-146a in myocardial ischaemia reperfusion injury and the underlying mechanism. C57BL/6J mice were subjected to 45 min of ischaemia and 1 week of reperfusion to establish a myocardial I/R injury model. A miR-146a mimic (0.5 mg/kg) was administered intravenously at the beginning of the ischaemia process. Neonatal rat cardiomyocytes were also subjected to hypoxia/reperfusion (H/R). Cells were treated with the miR-146a mimic or antagonist. As a result, the miR-146a mimic attenuated H/R-induced cardiomyocyte injury, as evidenced by increased cell viability and reduced lactate dehydrogenase (LDH) levels. In addition, the miR-146a mimic inhibited oxidative stress in cells suffering from H/R injury. Moreover, the miR-146a antagonist exerted adverse effects in vitro. In mice with myocardial I/R injury, the miR-146a mimic preserved cardiac function and reduced the infarction area and fibrosis. Moreover, the miR-146a mimic decreased the inflammatory response and reactive oxygen species (ROS) accumulation in mouse hearts. Mechanistically, we found that miR-146a directly regulated the transcription of NOX4, which subsequently affected P38 signalling in cardiomyocytes. When we knocked down NOX4, the effects of the miR-146a antagonist in worsening the cell condition were counteracted in in vitro experiments. Taken together, the results suggest that miR-146a protects against myocardial ischaemia reperfusion injury by inhibiting NOX4 signalling. The miR-146a mimic may become a potential therapeutic approach for patients with myocardial ischaemia reperfusion.

scholarly journals The IL-2/Anti-IL-2 Complex Attenuates Cardiac Ischaemia-Reperfusion Injury Through Expansion of Regulatory T Cells

2017 ◽  
Vol 44 (5) ◽  
pp. 1810-1827 ◽  
Author(s):  
Junhui Xiao ◽  
Kunwu Yu ◽  
Ming Li ◽  
Chuanyin Xiong ◽  
Yuzhen Wei ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Reperfusion Injury ◽  
Sham Group ◽  
Myocardial Function ◽  
Ex Vivo ◽  
Inflammatory Factors ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Infarct Area

Background/Aims: Regulatory T cells (Tregs) can suppress immunologic damage in myocardial ischaemia/reperfusion injury (MIRI), however, the isolation and ex vivo expansion of these cells for clinical application remains challenging. Here, we investigated whether the IL-2/anti-IL-2 complex (IL-2C), a mediator of Treg expansion, can attenuate MIRI in mice. Methods: Myocardial I/R was surgically induced in male C57BL/6 mice, aged 8-10 weeks, that were randomly assigned to 1) sham group (Sham), 2) Phosphate Buffered Saline (PBS), 3) IL-2-anti-IL-2 Ab complex (IL-2C), or 4) sham group, 5) PBS, 6) IL-2C after MIRI, or 7) IL-2C, 8) IL-2C+anti-CD25 mAbs, or 9) IL-2C; 10) IL-2C+anti-TGF-β1 mAbs, 11) IL-2C+anti-IL-10 mAbs. The following parameters were measured at different time points: infarct area, myocardial apoptosis, splenocytes, the inhibitory function of Tregs, and presence of inflammatory factors. In addition, immunohistochemistry analysis was performed. Results: We observed that Tregs were activated in response to MIRI. IL-2C administered before MIRI induced Treg expansion in both spleen and heart, attenuated Th1 and Th17 cell numbers, improved myocardial function, and attenuated both infiltration of inflammatory cells and apoptosis after MIRI. Furthermore, IL-2C administration reduced expression of inflammatory cytokines in the heart and attenuated proliferation of splenic cells. Depletion of Tregs with anti-CD25 mAb abrogated the beneficial effects of IL-2C. However, IL-2C–mediated myocardial protection was not dependent on either IL-10 or TGF-β. In addition, IL-2C administration after MIRI did not reduce infarct area, but did improve myocardial function slightly and reduced myocardial fibrosis. Conclusion: Our results demonstrate that IL-2C–induced Treg expansion attenuates MIRI and improves myocardial recovery in vivo, suggesting that IL-2C is a promising therapeutic target for myocardial IRI.

scholarly journals Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhen Qiu ◽  
Hao Ming ◽  
Shaoqing Lei ◽  
Bin Zhou ◽  
Bo Zhao ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
High Glucose ◽  
Clock Genes ◽  
Diabetic Rats ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
The Stability

AbstractThe circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the expression pattern of the circadian nuclear receptor Rev-erbα to maintain the stability of circadian genes such as BMAL1. However, the mechanism by which the HDAC3-orchestrated Rev-erbα/BMAL1 pathway increases MI/RI in diabetes and its relationship with mitophagy have yet to be elucidated. Here, we observed that the clock genes Rev-erbα, BMAL1, and C/EBPβ oscillations were altered in the hearts of rats with streptozotocin (STZ)-induced diabetes, with upregulated HDAC3 expression. Oscillations of Rev-erbα and BMAL1 were rapidly attenuated in diabetic MI/R hearts versus non-diabetic I/RI hearts, in accordance with impaired and rhythm-disordered circadian-dependent mitophagy that increased injury. Genetic knockdown of HDAC3 significantly attenuated diabetic MI/RI by mediating the Rev-erbα/BMAL1 circadian pathway to recover mitophagy. Primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA were exposed to hypoxia/reoxygenation (H/R) in vitro. The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high-glucose conditions compared with low-glucose conditions, with decreased BMAL1 expression and mitophagy levels. After H/R stimulation, high glucose aggravated H/R injury, with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 and mitophagy levels. HDAC3 and Rev-erbα siRNA can alleviate high glucose-induced and H/R-induced injury by upregulating BMAL1 to increase mitophagy. Collectively, these findings suggest that disruption of HDAC3-mediated circadian gene expression oscillations induces mitophagy dysfunction, aggravating diabetic MI/RI. Cardiac-specific HDAC3 knockdown could alleviate diabetic MI/RI by regulating the Rev-erbα/BMAL1 pathway to restore the activation of mitophagy.

Nitrite and myocardial ischaemia reperfusion injury. Where are we now?

2021 ◽  
Vol 223 ◽  
pp. 107819
Author(s):  
Kayleigh Griffiths ◽  
Jordan J. Lee ◽  
Michael P. Frenneaux ◽  
Martin Feelisch ◽  
Melanie Madhani
Keyword(s):  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion
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