scholarly journals Estrogen accelerates heart regeneration by promoting the inflammatory response in zebrafish

2020 ◽  
Vol 245 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Shisan Xu ◽  
Fangjing Xie ◽  
Li Tian ◽  
Samane Fallah ◽  
Fatemeh Babaei ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Cardiac Injury ◽  
Specific Protein ◽  
Sexual Differences ◽  
Heart Regeneration ◽  
Underlying Mechanisms ◽  
Female Specific ◽  
Estrogen Antagonist ◽  
Zebrafish Heart

Sexual differences have been observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogen-antagonist tamoxifen. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a. The resulting endocrine disruption induces the expression of the female-specific protein vitellogenin in male zebrafish. Transcriptomic analyses suggested heart injuries triggered pronounced immune and inflammatory responses in females. These responses, previously shown to elicit heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in females. Furthermore, a prior exposure to estrogen preconditioned the zebrafish heart for an accelerated regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to cardiac injury. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provide a new model system for the study of sexual differences in human cardiac repair.

scholarly journals Estrogen accelerates heart regeneration by promoting inflammatory responses in zebrafish

2019 ◽  
Author(s):  
Shisan Xu ◽  
Fangjing Xie ◽  
Samane Fallah ◽  
Fatemeh Babaei ◽  
Lina Zhu ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Specific Protein ◽  
Model System ◽  
Sexual Differences ◽  
Heart Regeneration ◽  
Heart Injury ◽  
Underlying Mechanisms ◽  
Female Specific ◽  
Estrogen Antagonist ◽  
Zebrafish Heart

AbstractSexual differences are observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we report that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and suppressed by estrogen-antagonist tamoxifen. Injuries to the heart, but not other tissues, increased plasma estrogen level and expression of estrogen receptors, especiallyesr2a, in zebrafish hearts. The resulting endocrine disruption induces the expression of female-specific protein vitellogenin in male zebrafish. Transcriptomic analyses suggested heart injuries triggered more pronounced immune and inflammatory responses in females. These responses, previously shown to enhance heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in female. Furthermore, a brief exposure to estrogen could precondition zebrafish for an accelerated heart regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to heart injury. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provides a new model system for the study of sexual differences in human cardiac repair.

scholarly journals Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Matthew Gemberling ◽  
Ravi Karra ◽  
Amy L Dickson ◽  
Kenneth D Poss
Keyword(s):  
Cardiac Injury ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Adult Zebrafish ◽  
Perivascular Cells ◽  
Adult Heart ◽  
Muscle Hyperplasia ◽  
Zebrafish Heart

Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.

scholarly journals Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish

2019 ◽  
Vol 116 (7) ◽  
pp. 1357-1371 ◽  
Author(s):  
Laura Bevan ◽  
Zhi Wei Lim ◽  
Byrappa Venkatesh ◽  
Paul R Riley ◽  
Paul Martin ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Cardiac Injury ◽  
Repair Process ◽  
Adult Zebrafish ◽  
Cardiac Damage ◽  
Scar Resolution ◽  
Macrophage Subsets

Abstract Aims A robust inflammatory response to tissue injury is a necessary part of the repair process but the deposition of scar tissue is a direct downstream consequence of this response in many tissues including the heart. Adult zebrafish not only possess the capacity to regenerate lost cardiomyocytes but also to remodel and resolve an extracellular scar within tissues such as the heart, but this scar resolution process remains poorly understood. This study aims to characterize the scarring and inflammatory responses to cardiac damage in adult zebrafish in full and investigate the role of different inflammatory subsets specifically in scarring and scar removal. Methods and results Using stable transgenic lines, whole organ imaging and genetic and pharmacological interventions, we demonstrate that multiple inflammatory cell lineages respond to cardiac injury in adult zebrafish. In particular, macrophage subsets (tnfα+ and tnfα−) play prominent roles with manipulation of different phenotypes suggesting that pro-inflammatory (tnfα+) macrophages promote scar deposition following cardiac injury whereas tnfα− macrophages facilitate scar removal during regeneration. Detailed analysis of these specific macrophage subsets reveals crucial roles for Csf1ra in promoting pro-inflammatory macrophage-mediated scar deposition. Additionally, the multifunctional cytokine Osteopontin (Opn) (spp1) is important for initial scar deposition but also for resolution of the inflammatory response and in late-stage ventricular collagen remodelling. Conclusions This study demonstrates the importance of a correctly balanced inflammatory response to facilitate scar deposition during repair but also to allow subsequent scar resolution, and full cardiac regeneration, to occur. We have identified Opn as having both pro-fibrotic but also potentially pro-regenerative roles in the adult zebrafish heart, driving Collagen deposition but also controlling inflammatory cell resolution.

Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway

2021 ◽  
Author(s):  
Guocheng Ren ◽  
Qiujie Zhou ◽  
Meili Lu ◽  
Hongxin Wang
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Cardiac Injury ◽  
H9c2 Cells ◽  
Sod Activity ◽  
Lps Challenge ◽  
Pathway Activation ◽  
Underlying Mechanisms

The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide(LPS)-challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the NLRP3/TLR4 pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocytes injury was markedly attenuated by rosuvastatin treatment. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells cotreated with rosuvastatin. In addition, excessive oxidative stress was present, as indicated by increases in MDA content, NADPH activity and ROS production and decreased SOD activity after LPS challenge. Rosuvastatin improved all the indicators of oxidative stress, with a similar effect to NAC(ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/NF-κB pathway activation. Administration of rosuvastatin reduced the increases in expression of NLRP3, ASC, pro-caspase-1, TLR4, and p65 and decreased the contents of TNF-α, IL-1β, IL-18 and IL-6, with a similar effect as MCC950 (NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotection of rosuvastatin on cardiac injury induced by LPS, and the effect of rosuvastatin was achieved by inactivation of the NF-κB/NLRP3 pathway

scholarly journals Myocardial NF-κB activation is essential for zebrafish heart regeneration

2015 ◽  
Vol 112 (43) ◽  
pp. 13255-13260 ◽  
Author(s):  
Ravi Karra ◽  
Anne K. Knecht ◽  
Kazu Kikuchi ◽  
Kenneth D. Poss
Keyword(s):  
Tissue Regeneration ◽  
Therapeutic Strategy ◽  
Cardiac Injury ◽  
Regulatory Sequences ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Developmental Program ◽  
Lower Vertebrates ◽  
Outstanding Question ◽  
Zebrafish Heart

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.

scholarly journals Induction of Wnt signaling antagonists and P21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration

2020 ◽  
Author(s):  
Xiangwen Peng ◽  
Kaa Seng Lai ◽  
Peilu She ◽  
Junsu Kang ◽  
Tingting Wang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Cardiac Tissue ◽  
Cardiac Injury ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiac Damage ◽  
Ectopic Activation ◽  
P21 Activated Kinase ◽  
Wnt Inhibitors ◽  
Zebrafish Heart

Abstract Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that P21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic β-catenin at Ser675 and increases its stability at disassembled sarcomeres during regeneration. Myocardial-specific induction of the phospho-mimetic β-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to cardiac damage. Importantly, inactivation of Pak2 kinase activity reduces the Ser675-phosphorylated β-catenin (pS675-β-catenin) at cardiac wounds and attenuates CM sarcomere disorganization, dedifferentiation, and proliferation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-β-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.

Physical exercise as a human model of limited inflammatory response

1998 ◽  
Vol 76 (5) ◽  
pp. 589-597 ◽  
Author(s):  
Pang N Shek ◽  
Roy J Shephard
Keyword(s):  
Physical Exercise ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Active Phase ◽  
Human Model ◽  
Inflammatory Factors ◽  
Trauma Patients ◽  
Inflammatory Reactions ◽  
Underlying Mechanisms

An inflammatory response represents a fundamental series of humoral and cellular reaction cascades in response to infection, tissue injury, and related insults. An excessive response is commonly seen under the pathological conditions of trauma, sepsis, and burns. It is becoming increasingly evident that most, if not all, of the distinguishing features of a classical inflammatory response are detectable in an exercising individual, namely mobilization and activation of granulocytes, lymphocytes, and monocytes; release of inflammatory factors and soluble mediators; involvement of active phase reactants; and activation of the complement and other reactive humoral cascade systems. While the manifestation of many exercise-induced immune and related changes has been reported and confirmed repeatedly, the underlying mechanisms triggering and modulating the elicited immune responses are, at best, poorly understood. Unlike the exaggerated and sometimes uncontrollable inflammatory response in septic and trauma patients resulting in morbidity and mortality, strenuous and severe exercise normally elicits an inflammatory response of a subclinical nature to facilitate the repairing process for site-specific tissue damage. Regardless of the inciting event, for example trauma, infection, or exercise, and given an appropriate triggering signal, a remarkably similar sequence of inflammatory reactions can be reproduced in the affected host. Therefore, physical exercise and training represent an acceptable and good model for the study of limited inflammatory responses in humans.Key words: trauma, infection, exercise, inflammatory response, cytokines.

scholarly journals Midkine-a regulates the formation of a fibrotic scar during zebrafish heart regeneration

2021 ◽  
Author(s):  
Dimitrios Grivas ◽  
Álvaro González-Rajal ◽  
José Luis de la Pompa
Keyword(s):  
Critical Role ◽  
Cardiac Injury ◽  
Transcriptional Analysis ◽  
Endothelial Cell Proliferation ◽  
Heart Regeneration ◽  
Knock Out ◽  
Tgfβ Signalling ◽  
Fibrotic Scar ◽  
Zebrafish Heart

AbstractThe adult zebrafish heart regenerates after injury, unlike the hearts of mammals. Heart cryoinjury triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of mdka in zebrafish heart regeneration. We show that mdka expression is strongly induced at 1-day post cryoinjury (dpci) throughout the epicardium, whereas by 7 dpci expression has become restricted to epicardial cells covering the injured area. To study the role of mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka decreased endothelial cell proliferation and resulted in a blockade of heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and TGFβ signalling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.

scholarly journals Midkine-a Regulates the Formation of a Fibrotic Scar During Zebrafish Heart Regeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Dimitrios Grivas ◽  
Álvaro González-Rajal ◽  
José Luis de la Pompa
Keyword(s):  
Critical Role ◽  
Cardiac Injury ◽  
Transcriptional Analysis ◽  
Endothelial Cell Proliferation ◽  
Heart Regeneration ◽  
Knock Out ◽  
Injured Area ◽  
Fibrotic Scar ◽  
Zebrafish Heart

Unlike the hearts of mammals, the adult zebrafish heart regenerates after injury. Heart cryoinjury in zebrafish triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of mdka in zebrafish heart regeneration. We show that mdka expression was induced at 1-day post-cryoinjury (dpci) throughout the epicardial layer, whereas by 7 dpci expression had become restricted to the epicardial cells covering the injured area. To study the role of mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka decreased endothelial cell proliferation and resulted in an arrest in heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and intense TGFβ signaling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.

MicroRNA-96 is downregulated in sepsis neonates and attenuates LPSinduced inflammatory response by inhibiting IL-16 in monocytes

2020 ◽  
Vol 23 ◽  
Author(s):  
Chunlei Zhang ◽  
Xiuting Li ◽  
Na Liu ◽  
Zijian Feng ◽  
Chengyuan Zhang
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Diagnostic Value ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Real Time Quantitative Pcr ◽  
Non Invasive ◽  
Causes Of Mortality ◽  
Underlying Mechanisms ◽  
Relationship Of

Background: Neonatal sepsis (NS) remains one of the leading causes of mortality among newborns. This study found the deregulated microRNA-96 (miR-96) in NS neonates, and aimed to evaluate the clinical significance of miR-96, as well as its effect on LPS-induced inflammatory response in monocytes. In addition, the relationship of interleukin-16 (IL16) and miR-96 was investigated to understand the underlying mechanisms. Methods: Expression of miR-96 was examined using real-time quantitative PCR. Monocytes stimulated by LPS was used to mimic excessive inflammation in the pathogenesis of NS. The enzyme-linked immunosorbent assay was applied to evaluate pro-inflammatory cytokines levels. A luciferase reporter assay was used to confirm the interaction between miR-96 and IL16. Results: Serum miR-96 expression was decreased in NS newborns and had considerable diagnostic value for NS screening. LPS inhibited miR-96 expression in monocytes, and the overexpression of miR-96 could reverse the effects of LPS on the inflammation of monocytes. IL-16 was a target gene of miR-96 and negatively correlated with miR-96 levels in NS neonates. The inhibited inflammatory responses induced by miR-96 overexpression was abolished by the elevated IL-16 in monocytes. Conclusion: All the data reveal that serum decreased miR-96 may serve as a candidate non-invasive biomarker for NS diagnosis. In addition, miR-96 inhibits LPS-induced inflammatory responses by targeting IL-16 in monocytes. The miR96/IL-16 axis may provide novel therapeutic targets for NS treatment.

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