Temporal dynamics of immune response following prolonged myocardial ischemia/reperfusion with and without cyclosporine A

Rusinkevich, Vitali; Huang, Yin; Chen, Zhongyan; Wu, Qiang; Wang, Yigang; Shi, Yufang; Yang, Huang‐Tian

doi:10.1038/s41401-018-0197-1

Cited by 38 publications

(39 citation statements)

References 50 publications

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“…Scrutiny of the relative timings of cytokine elevation after ischaemic injury in relation to neutrophil mobilisation does not support their role in this early mobilisation, since both the onset and peaks in neutrophil mobilisation occur prior to those for cytokine elevation (17, 18, 43) . IL-8 injection mobilised neutrophils from the bone marrow (13) , but after reperfusion in AMI, even in blood from the coronary sinus (undiluted myocardial effluent), the elevation is modest (0.1-fold) (18, 19) .…”

Section: Discussionmentioning

confidence: 97%

“…The bone marrow has been regarded as the principal source for neutrophils that are mobilised to peripheral blood after injury, because (i) it is the primary site for granulopoiesis (8-10) ; (ii) it contains ample reserves of mature cells and; (iii) releases neutrophils in response to injection of exogenous chemokines (12-16) . However, the divergent timings of neutrophil mobilisation (rapid) (1, 20) and chemokine elevation (delayed) in vivo (17, 18, 43) suggest that additional processes may be involved.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial Cell-Derived Extracellular Vesicles Elicit Neutrophil Deployment From the Spleen Following Acute Myocardial Infarction

Akbar

Braithwaite

Corr

et al. 2020

Preprint

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Acute myocardial infarction rapidly increases blood neutrophils (<2 hours). Release of neutrophils from bone marrow, in response to chemokine elevation, has been considered their source, but chemokine levels peak up to 24 hours after injury, and after neutrophil elevation. This suggests that additional non chemokine-dependent processes may be involved. Endothelial cell (EC) activation promotes the rapid (<30 minutes) release of extracellular vesicles (EVs), which are enriched in vascular cell adhesion molecule-1 (VCAM-1) and miRNA-126, and are thus a potential mechanism for communicating with remote tissues. Here, we show that injury to the myocardium rapidly mobilises neutrophils from the spleen to peripheral blood and induces their transcriptional activation prior to their arrival at injured tissue. Ischemic myocardium leads to the generation and release of EC-derived-EVs bearing VCAM-1. EC-EV delivery to the spleen alters inflammatory gene and chemokine protein expression, and mobilises neutrophils to peripheral blood. Using CRISPR/Cas9 genome editing we generated VCAM-1-deficient EV and showed that its deletion removed the ability of EC-EV to provoke the mobilisation of neutrophils. Furthermore, inhibition of miRNA-126 in vivo reduced myocardial infarction size in a mouse model. Our findings show a novel mechanism for the rapid mobilisation of neutrophils to peripheral blood from a splenic reserve, independent of classical chemokine signalling, and establish a proof of concept for functional manipulation of EV-communications through genetic alteration of parent cells.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Endothelial Cell-Derived Extracellular Vesicles Elicit Neutrophil Deployment From the Spleen Following Acute Myocardial Infarction

Akbar

Braithwaite

Corr

et al. 2020

Preprint

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“…In a mouse model of MI with permanent coronary ligation, we showed that activated CD8 + T cells expressing CD69 and CD107a markers were recruited within the ischemic myocardium. Such CD8 + T cell in ltration in the heart has also been observed in experimental transient ischemia 27 . In humans, CD8 + T cells were identi ed in the ischemic heart tissue at early stage after MI, but predominated in the periinfarct region one week after MI.…”

Section: Discussionmentioning

confidence: 58%

Cytotoxic CD8+ T Cells Promote Granzyme B-Dependent Adverse Post-Ischemic Cardiac Remodeling

Zas

Lemarié

Zlatanova

et al. 2020

Preprint

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Acute myocardial infarction (MI) is a common condition responsible for heart failure and sudden death. Here, we show that following acute MI in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue, and release Granzyme B leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function was confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of Granzyme B in patients with acute MI predict increased risk of death at 1-year follow-up. Our work unravels an unsuspected deleterious role of CD8+ T lymphocytes following acute ischemia, and identifies novel therapeutic strategy targeting pathogenic CD8+ T lymphocytes in the setting of acute MI.

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“…However, both pathophysiological conditions cause extensive tissue injury associated with the inflammatory response at ischemic and non-ischemic areas after MI. Indeed, neutrophils and inflammatory cytokines significantly increased in the heart at 1 day after permanent occlusion of LCA and myocardial I/R [47][48][49] . In the previous reports, suppression of the inflammatory response including infiltrating neutrophils decreased myocardial infarct size and improved cardiac function in permanent occlusion of LCA 50,51 and myocardial I/R 52,53 .…”

Section: Discussionmentioning

confidence: 99%

Effects of progranulin on the pathological conditions in experimental myocardial infarction model

Sasaki

Shimazawa

Kanamori

et al. 2020

Sci Rep

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Progranulin is a secreted growth factor associated with multiple physiological functions in ischemic pathophysiology. However, it is still not fully understood how progranulin is involved in ischemic lesion and cardiac remodeling after myocardial infarction (MI). In this study, we investigated the effects of progranulin on myocardial ischemia and reperfusion injury. We investigated progranulin expression using Western blotting and immunostaining after permanent left coronary artery (LCA) occlusion in mice. Infarct size and the number of infiltrating neutrophils were measured 24 h after permanent LCA occlusion. Recombinant mouse progranulin was administered before LCA occlusion. In addition, we evaluated cardiac function using cardiac catheterization and echocardiography, and fibrosis size by Masson's trichrome staining after myocardial ischemia/reperfusion in rabbits. Recombinant human progranulin was administered immediately after induction of reperfusion. Progranulin expression increased in the myocardial ischemic area 1, 3, and 5 days after permanent LCA occlusion in mice. The administration of recombinant mouse progranulin significantly attenuated infarct size and infiltrating neutrophils 24 h after permanent LCA occlusion in mice. We also found that administration of recombinant human progranulin ameliorated the deterioration of cardiac dysfunction and fibrosis after myocardial ischemia/reperfusion in rabbits. These findings suggest that progranulin may protect myocardial ischemia/reperfusion injury. Cardiovascular diseases (CVD) are disorders of the heart and blood vessels, and a leading cause of death worldwide despite therapeutic intervention 1. The worldwide prevalence of CVD is approximately 17.7 million people every year, and CVD accounts for 30% of global mortality 2. Acute myocardial infarction (AMI) in CVD leads to the sudden cardiac death and heart failure, which is a devastating complication 3. AMI is an event of myocardial necrosis by acute thrombotic obstructions of blood flow in coronary arteries. Rapid reperfusion of coronary arteries achieved by percutaneous coronary intervention (PCI) and thrombolysis benefits patients with AMI 4,5. However, there are several problems with current therapy. Myocardial ischemia/reperfusion (I/R) injury increases myocardial infarct size and decreases blood flow associated with microcirculatory disturbances 6-8. Enlargement of I/R injury from delayed reperfusion therapy increases the risk of subsequent developments of cardiac rupture and heart failure, in patients with AMI 7. In addition, these therapies and subsequent therapeutic interventions increase the mental and economic burden on patients 9,10. Therefore, it is important to elucidate the pathogenesis of myocardial I/R injury and explore novel therapeutic targets for AMI. Progranulin is a secreted growth factor associated with embryonic development 11 , wound healing 12 , and inflammation 13,14. Progranulin expression is observed in macrophages, neutrophils and skeletal myocytes 15,16 .

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Temporal dynamics of immune response following prolonged myocardial ischemia/reperfusion with and without cyclosporine A

Cited by 38 publications

References 50 publications

Endothelial Cell-Derived Extracellular Vesicles Elicit Neutrophil Deployment From the Spleen Following Acute Myocardial Infarction

Endothelial Cell-Derived Extracellular Vesicles Elicit Neutrophil Deployment From the Spleen Following Acute Myocardial Infarction

Cytotoxic CD8+ T Cells Promote Granzyme B-Dependent Adverse Post-Ischemic Cardiac Remodeling

Effects of progranulin on the pathological conditions in experimental myocardial infarction model

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