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

Background: Ischemia reperfusion injury (IRI) predisposes to the formation of donor-specific antibodies, a factor contributing to chronic rejection and late allograft loss. Methods: We describe a mechanism underlying the correlative association between IRI and donor-specific antibodies by using humanized models and patient specimens. Results: IRI induces immunoglobulin M–dependent complement activation on endothelial cells that assembles an NLRP3 (NOD-like receptor pyrin domain-containing protein 3) inflammasome via a Rab5-ZFYVE21-NIK axis and upregulates ICOS-L (inducible costimulator ligand) and PD-L2 (programmed death ligand 2). Endothelial cell–derived interleukin-18 (IL-18) selectively expands a T-cell population (CD4+CD45RO+PD-1 hi ICOS+CCR2+CXCR5–) displaying features of recently described T peripheral helper cells. This population highly expressed IL-18R1 and promoted donor-specific antibodies in response to IL-18 in vivo. In patients with delayed graft function, a clinical manifestation of IRI, these cells were Ki-67+IL-18R1+ and could be expanded ex vivo in response to IL-18. Conclusions: IRI promotes elaboration of IL-18 from endothelial cells to selectively expand alloreactive IL-18R1+ T peripheral helper cells in allograft tissues to promote donor-specific antibody formation.

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Endothelial Cell Activation in an Embolic Ischemia-Reperfusion Injury Microfluidic Model

Micromachines ◽

10.3390/mi10120857 ◽

2019 ◽

Vol 10 (12) ◽

pp. 857 ◽

Cited By ~ 1

Author(s):

Danielle Nemcovsky Amar ◽

Mark Epshtein ◽

Netanel Korin

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Reperfusion Injury ◽

Cell Activation ◽

Ischemia Reperfusion Injury ◽

Blood Clot ◽

Ischemia Reperfusion ◽

Clot Lysis ◽

Endothelial Cell Activation ◽

Myocardial Infraction

Ischemia, lack of blood supply, is associated with a variety of life-threatening cardiovascular diseases, including acute ischemic stroke and myocardial infraction. While blood flow restoration is critical to prevent further damage, paradoxically, rapid reperfusion can increase tissue damage. A variety of animal models have been developed to investigate ischemia/reperfusion injury (IRI), however they do not fully recapitulate human physiology of IRI. Here, we present a microfluidic IRI model utilizing a vascular compartment comprising human endothelial cells, which can be obstructed via a human blood clot and then re-perfused via thrombolytic treatment. Using our model, a significant increase in the expression of the endothelial cell inflammatory surface receptors E-selectin and I-CAM1 was observed in response to embolic occlusion. Following the demonstration of clot lysis and reperfusion via treatment using a thrombolytic agent, a significant decrease in the number of adherent endothelial cells and an increase in I-CAM1 levels compared to embolic occluded models, where reperfusion was not established, was observed. Altogether, the presented model can be applied to allow better understanding of human embolic based IRI and potentially serve as a platform for the development of improved and new therapeutic approaches.

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Endothelial Cell Cystathionine γ‐Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury

Journal of the American Heart Association ◽

10.1161/jaha.120.017544 ◽

2020 ◽

Vol 9 (19) ◽

Author(s):

Huijing Xia ◽

Zhen Li ◽

Thomas E. Sharp ◽

David J. Polhemus ◽

Jean Carnal ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Reperfusion Injury ◽

Exercise Capacity ◽

Vascular Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Ischemia Reperfusion Injury ◽

Genetic Deletion ◽

Myocardial Ischemia Reperfusion

Background Hydrogen sulfide (H 2 S) is an important endogenous physiological signaling molecule and exerts protective properties in the cardiovascular system. Cystathionine γ‐lyase (CSE), 1 of 3 H 2 S producing enzyme, is predominantly localized in the vascular endothelium. However, the regulation of CSE in vascular endothelium remains incompletely understood. Methods and Results We generated inducible endothelial cell‐specific CSE overexpressed transgenic mice (EC‐CSE Tg) and endothelial cell‐specific CSE knockout mice (EC‐CSE KO), and investigated vascular function in isolated thoracic aorta, treadmill exercise capacity, and myocardial injury following ischemia‐reperfusion in these mice. Overexpression of CSE in endothelial cells resulted in increased circulating and myocardial H 2 S and NO, augmented endothelial‐dependent vasorelaxation response in thoracic aorta, improved exercise capacity, and reduced myocardial‐reperfusion injury. In contrast, genetic deletion of CSE in endothelial cells led to decreased circulating H 2 S and cardiac NO production, impaired endothelial dependent vasorelaxation response and reduced exercise capacity. However, myocardial‐reperfusion injury was not affected by genetic deletion of endothelial cell CSE. Conclusions CSE‐derived H 2 S production in endothelial cells is critical in maintaining endothelial function, exercise capacity, and protecting against myocardial ischemia/reperfusion injury. Our data suggest that the endothelial NO synthase—NO pathway is likely involved in the beneficial effects of overexpression of CSE in the endothelium.

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