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 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 The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase

Development ◽  
2020 ◽  
Vol 147 (18) ◽  
pp. dev190678
Author(s):  
Peilu She ◽  
Huifang Zhang ◽  
Xiangwen Peng ◽  
Jianjian Sun ◽  
Bangjun Gao ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Transcriptional Repressor ◽  
Heart Regeneration ◽  
Protein Levels ◽  
Helix Loop Helix ◽  
Lysine Methyltransferase ◽  
Heart Injury ◽  
Potential Strategy ◽  
Phosphorylated Stat3 ◽  
Zebrafish Heart

ABSTRACTTeleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in gridlock (grl; also known as hey2), encoding a Hairy-related basic helix-loop-helix transcriptional repressor, enhance CM proliferation and reduce fibrosis following damage. In contrast, myocardial grl induction blunts CM dedifferentiation and regenerative responses to heart injury. RNA sequencing analyses uncover Smyd2 lysine methyltransferase (KMT) as a key transcriptional target repressed by Grl. Reduction in Grl protein levels triggered by injury induces smyd2 expression at the wound myocardium, enhancing CM proliferation. We show that Smyd2 functions as a methyltransferase and modulates the Stat3 methylation and phosphorylation activity. Inhibition of the KMT activity of Smyd2 reduces phosphorylated Stat3 at cardiac wounds, suppressing the elevated CM proliferation in injured grl mutant hearts. Our findings establish an injury-specific transcriptional repression program in governing CM renewal during heart regeneration, providing a potential strategy whereby silencing Grl repression at local regions might empower regeneration capacity to the injured mammalian heart.

scholarly journals Inhibition of let-7c Regulates Cardiac Regeneration after Cryoinjury in Adult Zebrafish

2019 ◽  
Vol 6 (2) ◽  
pp. 16 ◽  
Author(s):  
Suneeta Narumanchi ◽  
Karri Kalervo ◽  
Sanni Perttunen ◽  
Hong Wang ◽  
Katariina Immonen ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Regeneration ◽  
Nuclear Antigen ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Tissue Samples ◽  
Micro Rnas ◽  
Proliferating Cell ◽  
Zebrafish Heart

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration.

scholarly journals A Systematic Exposition of Methods used for Quantification of Heart Regeneration after Apex Resection in Zebrafish

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 548 ◽  
Author(s):  
Helene Juul Belling ◽  
Wolfgang Hofmeister ◽  
Ditte Caroline Andersen
Keyword(s):  
Human Heart ◽  
Quantitative Methods ◽  
Heart Function ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Ability To Regenerate ◽  
Specific Proteins ◽  
Heart Injury ◽  
Whole Heart ◽  
Study Designs

Myocardial infarction (MI) is a worldwide condition that affects millions of people. This is mainly caused by the adult human heart lacking the ability to regenerate upon injury, whereas zebrafish have the capacity through cardiomyocyte proliferation to fully regenerate the heart following injury such as apex resection (AR). But a systematic overview of the methods used to evidence heart regrowth and regeneration in the zebrafish is lacking. Herein, we conducted a systematical search in Embase and Pubmed for studies on heart regeneration in the zebrafish following injury and identified 47 AR studies meeting the inclusion criteria. Overall, three different methods were used to assess heart regeneration in zebrafish AR hearts. 45 out of 47 studies performed qualitative (37) and quantitative (8) histology, whereas immunohistochemistry for various cell cycle markers combined with cardiomyocyte specific proteins was used in 34 out of 47 studies to determine cardiomyocyte proliferation qualitatively (6 studies) or quantitatively (28 studies). For both methods, analysis was based on selected heart sections and not the whole heart, which may bias interpretations. Likewise, interstudy comparison of reported cardiomyocyte proliferation indexes seems complicated by distinct study designs and reporting manners. Finally, six studies performed functional analysis to determine heart function, a hallmark of human heart injury after MI. In conclusion, our data implies that future studies should consider more quantitative methods eventually taking the 3D of the zebrafish heart into consideration when evidencing myocardial regrowth after AR. Furthermore, standardized guidelines for reporting cardiomyocyte proliferation and sham surgery details may be considered to enable inter study comparisons and robustly determine the effect of given genes on the process of heart regeneration.

Chia oil prevents chemical and immune-mediated inflammatory responses in mice: Evidence for the underlying mechanisms

2021 ◽  
Vol 149 ◽  
pp. 110703
Author(s):  
Juliana Cavalli ◽  
Mariana A. Freitas ◽  
Elaine C.D. Gonçalves ◽  
Guilherme P. Fadanni ◽  
Adara A. Santos ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Immune Mediated ◽  
Underlying Mechanisms ◽  
Chia Oil

scholarly journals AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamie Francisco ◽  
Yu Zhang ◽  
Yasuki Nakada ◽  
Jae Im Jeong ◽  
Chun-Yang Huang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Inflammatory Responses ◽  
Cardiac Fibroblasts ◽  
Hippo Pathway ◽  
Additional Stress ◽  
Myocardial Inflammation ◽  
Adeno Associated Virus ◽  
Ccl2 Expression ◽  
Underlying Mechanisms ◽  
The Hippo Pathway

AbstractFibrosis is a hallmark of heart disease independent of etiology and is thought to contribute to impaired cardiac dysfunction and development of heart failure. However, the underlying mechanisms that regulate the differentiation of fibroblasts to myofibroblasts and fibrotic responses remain incompletely defined. As a result, effective treatments to mitigate excessive fibrosis are lacking. We recently demonstrated that the Hippo pathway effector Yes-associated protein (YAP) is an important mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Yet, whether YAP activation in cardiac fibroblasts is sufficient to drive fibrosis, and how fibroblast YAP affects myocardial inflammation, a significant component of adverse cardiac remodeling, are largely unknown. In this study, we leveraged adeno-associated virus (AAV) to target cardiac fibroblasts and demonstrate that chronic YAP expression upregulated indices of fibrosis and inflammation in the absence of additional stress. YAP occupied the Ccl2 gene and promoted Ccl2 expression, which was associated with increased macrophage infiltration, pro-inflammatory cytokine expression, collagen deposition, and cardiac dysfunction in mice with cardiac fibroblast-targeted YAP overexpression. These results are consistent with other recent reports and extend our understanding of YAP function in modulating fibrotic and inflammatory responses in the heart.

Abstract 103: Mechanistic Interplay Between Cardioprotection And Heart Regeneration Mediated By The ER-bound Transcription Factor Nrf1

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Miao Cui ◽  
Atmanli Ayhan ◽  
Ning Liu ◽  
Rhonda S Bassel-duby ◽  
Eric N Olson
Keyword(s):  
Transcription Factor ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Induced Pluripotent Stem Cell ◽  
Redox Balance ◽  
Mouse Heart ◽  
Heart Regeneration ◽  
Neonatal Cardiomyocytes ◽  
Underlying Mechanisms

Cardiomyocyte loss is the underlying basis for a majority of heart diseases. Preventing cardiomyocytes from death (cardioprotection) and replenishing the lost myocardium (regeneration) are the central goals for heart repair. Although cardioprotection and heart regeneration have been traditionally thought to involve separate mechanisms, protection of cardiomyocytes from injury or disease stimuli is a prerequisite to any meaningful regenerative response. In our study, we sought to understand how neonatal cardiomyocytes cope with injury-induced stress to regenerate damaged myocardium and whether the underlying mechanisms could be leveraged to promote heart regeneration and repair in adults. Using spatial transcriptomic profiling, we visualized regenerative cardiomyocytes reconstituting damaged myocardium after ischemia, and found that they are marked by expression of Nrf1, an ER-bound stress responsive transcription factor. Single-nucleus RNA sequencing revealed that genetic deletion of Nrf1 prevented neonatal cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, overexpression of Nrf1 protected the adult mouse heart from ischemia/reperfusion injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from cardiotoxicity induced by the chemotherapeutic drug doxorubicin. The cardioprotective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and maintenance of redox balance. Taken together, our study uncovers a unique adaptive mechanism activated in response to injury that maintains the tissue homeostatic balance required for heart regeneration. Reactivating these mechanisms in the adult heart represents a potential therapeutic approach for cardiac repair.

Abstract 706: Changes in Translational Efficacy During Zebrafish Heart Regeneration

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Joseph A Goldman ◽  
Ariel Bazzini ◽  
Antonio Giraldez ◽  
Kenneth Poss
Keyword(s):  
Heart Regeneration ◽  
Zebrafish Heart

scholarly journals In vivo cardiac reprogramming contributes to zebrafish heart regeneration

Nature ◽  
2013 ◽  
Vol 498 (7455) ◽  
pp. 497-501 ◽  
Author(s):  
Ruilin Zhang ◽  
Peidong Han ◽  
Hongbo Yang ◽  
Kunfu Ouyang ◽  
Derek Lee ◽  
...  
Keyword(s):  
Heart Regeneration ◽  
Zebrafish Heart
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