scholarly journals Hydrogen Sulfide Promotes Cardiomyocyte Proliferation and Heart Regeneration via ROS Scavenging

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jianqiu Pei ◽  
Fang Wang ◽  
Shengqiang Pei ◽  
Ruifeng Bai ◽  
Xiangfeng Cong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Hydrogen Sulfide ◽  
Oxidative Dna Damage ◽  
Cardiac Injury ◽  
Protective Role ◽  
Neonatal Mouse ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Ros Scavenging ◽  
Old Mice

Neonatal mouse hearts can regenerate completely in 21 days after cardiac injury, providing an ideal model to exploring heart regenerative therapeutic targets. The oxidative damage by Reactive Oxygen Species (ROS) is one of the critical reasons for the cell cycle arrest of cardiomyocytes (CMs), which cause mouse hearts losing the capacity to regenerate in 7 days or shorter after birth. As an antioxidant, hydrogen sulfide (H2S) plays a protective role in a variety of diseases by scavenging ROS produced during the pathological processes. In this study, we found that blocking H2S synthesis by PAG (H2S synthase inhibitor) suspended heart regeneration and CM proliferation with ROS deposition increase after cardiac injury (myocardial infarction or apex resection) in 2-day-old mice. NaHS (a H2S donor) administration improved heart regeneration with CM proliferation and ROS elimination after myocardial infarction in 7-day-old mice. NaHS protected primary neonatal mouse CMs from H2O2-induced apoptosis and promoted CM proliferation via SOD2-dependent ROS scavenging. The oxidative DNA damage in CMs was reduced with the elimination of ROS by H2S. Our results demonstrated for the first time that H2S promotes heart regeneration and identified NaHS as a potent modulator for cardiac repair.

scholarly journals gp130 Controls Cardiomyocyte Proliferation and Heart Regeneration

Circulation ◽  
2020 ◽  
Vol 142 (10) ◽  
pp. 967-982
Author(s):  
Yandong Li ◽  
Jie Feng ◽  
Shen Song ◽  
Haotong Li ◽  
Huijun Yang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Gene Therapy ◽  
Rna Sequencing ◽  
Cardiac Injury ◽  
Oncostatin M ◽  
Functional Screening ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Adult Mice ◽  
Neonatal Heart

Background: A key cause of the high mortality of cardiovascular diseases is the cardiomyocyte inability to renew after cardiac injury. As a promising strategy to supplement functional myocytes for cardiac repair, there is a pressing need to understand the cellular and molecular mechanisms of heart regeneration. Methods: Seven genetic mouse lines were used: global OSM (oncostatin M) knockout, monocyte-/macrophage-specific OSM deletion, cardiomyocyte-specific lines, including OSM receptor deletion, gp130 (glycoprotein 130) deletion, gp130 activation, and Yap (yes-associated protein) ablation with gp130 activation mice. A series of molecular signaling experiments, including RNA sequencing, immunostaining, coimmunoprecipitation, and imaging flow cytometry, were conducted. Two models of cardiac injury, apical resection and myocardial infarction operation, were performed in neonatal, juvenile, and adult mice. Heart regeneration and cardiac function were evaluated by Masson staining and echocardiography, respectively. Gene recombinant adenovirus-associated virus was constructed and infected myocardial-infarcted mice as a gene therapy. Results: OSM was identified by RNA sequencing as a key upstream regulator of cardiomyocyte proliferation during neonatal heart regeneration in mice. Cardiomyocyte proliferation and heart regeneration were suspended in neonatal mice after cardiac injury when OSM was conditionally knockout in macrophages. The cardiomyocyte-specific deficiency of the OSM receptor heterodimers, OSM receptor and gp130, individually in cardiomyocytes reduced myocyte proliferation and neonatal heart regeneration. Conditional activation of gp130 in cardiomyocytes promoted cardiomyocyte proliferation and heart regeneration in juvenile and adult mice. Using RNA sequencing and functional screening, we found that Src mediated gp130-triggered cardiomyocyte proliferation by activating Yap (yes-associated protein) with Y357 phosphorylation independently of the Hippo pathway. Cardiomyocyte-specific deletion of Yap in Myh6-gp130 ACT mice blocked the effect of gp130 activation–induced heart regeneration in juvenile mice. Gene therapy with adenovirus-associated virus encoding constitutively activated gp130 promoted cardiomyocyte proliferation and heart regeneration in adult mice after myocardial infarction. Conclusions: Macrophage recruitment is essential for heart regeneration through the secretion of OSM, which promotes cardiomyocyte proliferation. As the coreceptor of OSM, gp130 activation is sufficient to promote cardiomyocyte proliferation by activating Yap through Src during heart regeneration. gp130 is a potential therapeutic target to improve heart regeneration after cardiac injury.

Abstract 303: Decreasing Microenvironment Stiffness Improves Exogenous Extracellular Matrix Induced Heart Regeneration in Neonatal Mouse

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Xinming Wang ◽  
Samuel Senyo
Keyword(s):  
Myocardial Infarction ◽  
Extracellular Matrix ◽  
Ejection Fraction ◽  
Heart Function ◽  
Neonatal Mouse ◽  
Mouse Heart ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Collagen Crosslinks ◽  
Cardiac Ventricle

Introduction: Transplanting cardiac extracellular matrix (ECM) has been demonstrated to influence healing in post-ischemic hearts. We propose that altering mechanical properties can stimulate a regenerative response in ECM-treated hearts. In this study, we investigate the role of mechanical unloading and solubilized ECM to modulate matrix-induced heart regeneration in low-regenerative P5 neonatal mice after acute myocardial infarction and mouse ventricle explants. Methods: P5 neonatal mouse heart stiffness was lowered by inhibiting formation of new collagen crosslinks. Solubilized fetal ECM was injected immediately after myocardial infarction (MI). Heart function and histology were conducted at week 3 post-MI. Cardiac ventricle explants were also used to investigate relevant signaling pathways. Results: We observed that lowering tissue stiffness increased the regenerative influence of fetal ECM treatment on heart function, fibrosis, and cardiomyocyte proliferation. Decrease heart stiffness inhibits fibrosis and better preserves heart function in fetal ECM treated hearts (Figure 1). We further provide evidence that yes-associated protein (Yap) signaling pathway plays a role in ECM-induced cardiomyocyte proliferation possibly through cytoskeleton polymerization.The results suggest that the native microenvironment stiffness, particularly with aging or post-ischemia, affects the therapeutic efficacy of drugs for heart disease. Figure 1 . Fetal ECM treatment P5 mouse hearts showed a higher ejection fraction in comparison with the control hearts at 3-weeks post-MI. Decreasing heart stiffness in P5 mouse heart further promoted increased ejection fraction in fetal ECM treated animals. (n=5, two-way ANOVA test and Tukey’s test, *p<0.05, ****p<0.0001.)

scholarly journals Emerging Roles for Immune Cells and MicroRNAs in Modulating the Response to Cardiac Injury

2019 ◽  
Vol 6 (1) ◽  
pp. 5 ◽  
Author(s):  
Adriana Rodriguez ◽  
Viravuth Yin
Keyword(s):  
Immune Cells ◽  
Cardiac Tissue ◽  
Heart Function ◽  
Cardiac Injury ◽  
Scar Tissue ◽  
Acute Injury ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiac Damage ◽  
Dynamic Interplay

Stimulating cardiomyocyte regeneration after an acute injury remains the central goal in cardiovascular regenerative biology. While adult mammals respond to cardiac damage with deposition of rigid scar tissue, adult zebrafish and salamander unleash a regenerative program that culminates in new cardiomyocyte formation, resolution of scar tissue, and recovery of heart function. Recent studies have shown that immune cells are key to regulating pro-inflammatory and pro-regenerative signals that shift the injury microenvironment toward regeneration. Defining the genetic regulators that control the dynamic interplay between immune cells and injured cardiac tissue is crucial to decoding the endogenous mechanism of heart regeneration. In this review, we discuss our current understanding of the extent that macrophage and regulatory T cells influence cardiomyocyte proliferation and how microRNAs (miRNAs) regulate their activity in the injured heart.

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 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 Polyploidy in Cardiomyocytes

2020 ◽  
Vol 126 (4) ◽  
pp. 552-565 ◽  
Author(s):  
Wouter Derks ◽  
Olaf Bergmann
Keyword(s):  
Cardiac Injury ◽  
Physiological Role ◽  
Cell Types ◽  
Cell Number ◽  
The Body ◽  
Cardiomyocyte Hypertrophy ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Hypertrophic Growth

The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial cell loss caused by cardiac injury. In mammals, cardiac growth by cell number expansion changes to growth by cardiomyocyte enlargement soon after birth, coinciding with a period in which most cardiomyocytes increase their DNA content by multinucleation and nuclear polyploidization. Although cardiomyocyte hypertrophy is often associated with these processes, whether polyploidy is a prerequisite or a consequence of hypertrophic growth is unclear. Both the benefits of cardiomyocyte enlargement over proliferative growth of the heart and the physiological role of polyploidy in cardiomyocytes are enigmatic. Interestingly, hearts in animal species with substantial cardiac regenerative capacity dominantly comprise diploid cardiomyocytes, raising the hypothesis that cardiomyocyte polyploidy poses a barrier for cardiomyocyte proliferation and subsequent heart regeneration. On the contrary, there is also evidence for self-duplication of multinucleated myocytes, suggesting a more complex picture of polyploidy in heart regeneration. Polyploidy is not restricted to the heart but also occurs in other cell types in the body. In this review, we explore the biological relevance of polyploidy in different species and tissues to acquire insight into its specific role in cardiomyocytes. Furthermore, we speculate about the physiological role of polyploidy in cardiomyocytes and how this might relate to renewal and 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.

Abstract 569: Both Young and Old ACE2-transgenic Mice are More Resistant to Cardiac Dysfunction Induced by Myocardial Infarction

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Juan Zhang ◽  
Yanfei Qi ◽  
Colleen Jeffery ◽  
Andrew Espejo ◽  
Mohan Raizada ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Renin Angiotensin System ◽  
Inflammatory Cells ◽  
Protective Role ◽  
Cardiac Damage ◽  
Monocytes And Macrophages ◽  
Old Mice ◽  
Young Mice

Background: Increased activity of the classic renin-angiotensin system (RAS) is associated with cardiovascular diseases (CVD) such as heart failure and hypertension. Angiotensin-converting enzyme 2 (ACE2) is reported to provide a protective role in CVD. In addition, there is a shift in the balance of the ACE2/Angiotensin-(1-7) axis towards the ACE/Angiotensin II axis during aging, making the cardiovascular system more vulnerable to damages. We hypothesized that global ACE2-overexpression could correct the imbalance between the two axes by providing a cardiovascular protective role against heart failure both in young and aged mice. Methods: Both young (10 weeks old) and old (12 months old) ACE2-transgenic and wild type (WT) mice underwent myocardial infarction surgery. Cardiac function was measured using echocardiography four weeks after MI. The number of circulating inflammatory cells (CD11b) in the blood for these animals was also measured using flow cytometry. Results: In the MI animals, the WT-old mice had a significant reduction in ejection fraction (47.67±4.23%: from 72.63±8.52% to 24.96±4.29%). However, the reduction in EF for ACE2-old mice was 37% lower (26.26±1.90%: from 60.06±7.56% to 29.18±5.66%) than that of WT-old mice. Meanwhile, the MI-induced decrease in EF of 14.60±1.56% for ACE2-young mice (from 59.09±8.38% to 44.49±6.82%) also was significantly less than the 26.97±1.21% reduction observed in WT-young mice (from 53.23±7.67% to 26.26±6.46%). Thus, ACE2 overexpression provides some protection of cardiac function from ischemia-induced injury in both young and old animals. Moreover, the circulating monocytes and macrophages in the blood of ACE2-young MI mice (22.65±6.86%) was also less than which observed in the WT control (31.37±4.90%), suggesting that there is less cardiac damage in these animals. Conclusions: Collectively, our observation suggests that global ACE2 overexpression has a consistent cardiac protection both in the young and old and as a result, the heart may be more resistant to heart failure damage during aging. This protective effect may be partly due to its systematic anti-inflammatory effect.

scholarly journals Metformin accelerates zebrafish heart regeneration by inducing autophagy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Fangjing Xie ◽  
Shisan Xu ◽  
Yingying Lu ◽  
Kin Fung Wong ◽  
Lei Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Systolic Function ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Systematic Evaluation ◽  
Autophagic Flux ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Clinical Value ◽  
Zebrafish Model

AbstractMetformin is one of the most widely used drugs for type 2 diabetes and it also exhibits cardiovascular protective activity. However, the underlying mechanism of its action is not well understood. Here, we used an adult zebrafish model of heart cryoinjury, which mimics myocardial infarction in humans, and demonstrated that autophagy was significantly induced in the injured area. Through a systematic evaluation of the multiple cell types related to cardiac regeneration, we found that metformin enhanced the autophagic flux and improved epicardial, endocardial and vascular endothelial regeneration, accelerated transient collagen deposition and resolution, and induced cardiomyocyte proliferation. Whereas, when the autophagic flux was blocked, then all these processes were delayed. We also showed that metformin transiently enhanced the systolic function of the heart. Taken together, our results indicate that autophagy is positively involved in the metformin-induced acceleration of heart regeneration in zebrafish and suggest that this well-known diabetic drug has clinical value for the prevention and amelioration of myocardial infarction.

Abstract 15756: Vascular Guidance of Cardiomyocyte Proliferation During Growth and Regeneration

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Paige DeBeneditts ◽  
Anish Karpurapu ◽  
Kyla Brezitski ◽  
Michael C Thomas ◽  
Ravi - Karra
Keyword(s):  
Large Scale ◽  
Nearest Neighbor ◽  
Critical Role ◽  
Cell Types ◽  
Neonatal Mouse ◽  
Angiogenic Factor ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiac Growth ◽  
Multiple Cell

Introduction: Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance. Hypothesis: We hypothesized that CECs are required for CM proliferation during growth and regeneration. Methods and Results: We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express Vegfr2 . To functionally link CEC and CM proliferation, we generated Cdh5-CreER T2 ; Vefgr2 flox/flox mice to genetically delete Vegfr2 from CECs. Compared to mice with intact Vegfr2 , loss of Vegfr2 from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when Vegfr2 is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor, Vegfa can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14). Conclusions: CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.

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