scholarly journals Inhibition of GSK-3 to induce cardiomyocyte proliferation: a recipe for in situ cardiac regeneration

2018 ◽  
Vol 115 (1) ◽  
pp. 20-30 ◽  
Author(s):  
Anand Prakash Singh ◽  
Prachi Umbarkar ◽  
Yuanjun Guo ◽  
Thomas Force ◽  
Manisha Gupte ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Cardiac Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Short Supply ◽  
Injured Myocardium ◽  
Proliferation And Differentiation ◽  
Potential Applications ◽  
Specific Deletion

Abstract With an estimated 38 million current patients, heart failure (HF) is a leading cause of morbidity and mortality worldwide. Although the aetiology differs, HF is largely a disease of cardiomyocyte (CM) death or dysfunction. Due to the famously limited amount of regenerative capacity of the myocardium, the only viable option for advanced HF patients is cardiac transplantation; however, donor’s hearts are in very short supply. Thus, novel regenerative strategies are urgently needed to reconstitute the injured hearts. Emerging data from our lab and others have elucidated that CM-specific deletion of glycogen synthase kinase (GSK)-3 family of kinases induces CM proliferation, and the degree of proliferation is amplified in the setting of cardiac stress. If this proliferation is sufficiently robust, one could induce meaningful regeneration without the need for delivering exogenous cells to the injured myocardium (i.e. cardiac regeneration in situ). Herein, we will discuss the emerging role of the GSK-3s in CM proliferation and differentiation, including their potential implications in cardiac regeneration. The underlying molecular interactions and cross-talk among signalling pathways will be discussed. We will also review the specificity and limitations of the available small molecule inhibitors targeting GSK-3 and their potential applications to stimulate the endogenous cardiac regenerative responses to repair the injured heart.

Role of GSK-3 in Cardiac Health: Focusing on Cardiac Remodeling and Heart Failure

2021 ◽  
Vol 22 ◽  
Author(s):  
Ubaid Tariq ◽  
Shravan Kumar Uppulapu ◽  
Sanjay K Banerjee
Keyword(s):  
Heart Failure ◽  
Cell Cycle ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Cardiac Regeneration ◽  
Negative Regulator ◽  
Cell Cycle Regulators ◽  
Cardiomyocyte Proliferation ◽  
Gsk 3Β

: Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and was first identified as a regulator of glycogen synthase enzyme and glucose homeostasis. It regulates cellular processes like cell proliferation, metabolism, apoptosis and development. Recent findings suggest that GSK-3 is required to maintain the normal cardiac homeostasis that regulates cardiac development, proliferation, hypertrophy and fibrosis. GSK-3 is expressed as two isoforms, α and β. Role of GSK-3α and GSK-3β in cardiac biology is well documented. Both isoforms have common as well as isoform-specific functions. Human data also suggests that GSK-3β is downregulated in hypertrophy and heart failure, and acts as a negative regulator. Pharmacological inhibition of GSK-3α and GSK-3β leads to the endogenous cardiomyocyte proliferation and cardiac regeneration by inducing the upregulation of cell cycle regulators, which results in cell cycle re-entry and DNA synthesis. It was found that cardiac specific knockout (KO) of GSK-3α retained cardiac function, inhibited cardiovascular remodelling and restricted scar expansion during ischemia. Further, knockout of GSK-3α decreases cardiomyocyte apoptosis and enhances its proliferation. However, GSK-3β KO also results in hypertrophic myopathy due to cardiomyocyte hyper-proliferation. Thus GSK-3 inhibitors are named as a double-edged sword because of their beneficial and off target effects. This review focuses on the isoform specific functions of GSK-3 that will help in better understanding about the role of GSK-3α and GSK-3β in cardiac biology and pave a way for the development of new isoform specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.

scholarly journals Cardiac regeneration: epicardial mediated repair

2015 ◽  
Vol 282 (1821) ◽  
pp. 20152147 ◽  
Author(s):  
Teresa Kennedy-Lydon ◽  
Nadia Rosenthal
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Cardiac Fibroblasts ◽  
Cardiac Regeneration ◽  
Repair Process ◽  
Regenerative Process ◽  
Cardiac Stem Cell ◽  
Cardiomyocyte Proliferation ◽  
Lower Vertebrates

The hearts of lower vertebrates such as fish and salamanders display scarless regeneration following injury, although this feature is lost in adult mammals. The remarkable capacity of the neonatal mammalian heart to regenerate suggests that the underlying machinery required for the regenerative process is evolutionarily retained. Recent studies highlight the epicardial covering of the heart as an important source of the signalling factors required for the repair process. The developing epicardium is also a major source of cardiac fibroblasts, smooth muscle, endothelial cells and stem cells. Here, we examine animal models that are capable of scarless regeneration, the role of the epicardium as a source of cells, signalling mechanisms implicated in the regenerative process and how these mechanisms influence cardiomyocyte proliferation. We also discuss recent advances in cardiac stem cell research and potential therapeutic targets arising from these studies.

scholarly journals Soluble Alpha-Klotho Alleviates Cardiac Fibrosis without Altering Cardiomyocytes Renewal

2020 ◽  
Vol 21 (6) ◽  
pp. 2186
Author(s):  
Wei-Yu Chen
Keyword(s):  
Endothelial Cells ◽  
Cardiac Fibrosis ◽  
Fibroblast Growth Factor 23 ◽  
Cardiac Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Injured Myocardium ◽  
H9c2 Cardiomyocytes ◽  
Mapping Models

Heart disease is the leading cause of death worldwide. The major cause of heart failure is the death of the myocardium caused by myocardial infarction, detrimental cardiac remodeling, and cardiac fibrosis occurring after the injury. This study aimed at discovering the role of the anti-aging protein α-klotho (KL), which is the co-receptor of fibroblast growth factor-23 (FGF23), in cardiac regeneration, fibrosis, and repair. We found that the anti-apoptotic function of soluble KL in isoproterenol-treated H9c2 cardiomyocytes was independent of FGF23 in vitro. In vivo, isoproterenol-induced cardiac fibrosis and cardiomyocyte and endothelial cell apoptosis were reduced by KL treatment. Moreover, the number of Ki67-positive endothelial cells and microvessel density within the isoproterenol-injured myocardium were increased upon KL treatment. However, by using genetic fate-mapping models, no evident cardiomyocyte proliferation within the injured myocardium was detected with or without KL treatment. Collectively, the cardioprotective functions of KL could be predominantly attributed to its anti-apoptotic and pro-survival activities on endothelial cells and cardiomyocytes. KL could be a potential cardioprotective therapeutic agent with anti-apoptotic and pro-survival activities on cardiomyocytes and endothelial cells.

P2586Cardiac progenitor cell exosome-associated periostin triggers reentry of cardiomyocytes into cell cycle

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Balbi ◽  
S Bolis ◽  
L Barile ◽  
G Vassalli
Keyword(s):  
Cell Cycle ◽  
Real Time ◽  
Western Blotting ◽  
Matrix Protein ◽  
Cardiac Regeneration ◽  
Extracellular Matrix Protein ◽  
Cardiomyocyte Proliferation ◽  
Rt Pcr ◽  
Swiss National Science Foundation

Abstract Introduction Nanovesicles known as exosomes (Exo) from cardiac-derived progenitor cells (CPCs) are cardioprotective and improve cardiac function after myocardial infarction; however the mechanisms of benefit are incompletely understood, especially with respect to endogenous cardiomyocytes (CM) renewal. Periostin (POSTN), a secreted extracellular matrix protein, is emerging as a matricellular factor that can trigger CM proliferation. We have identified POSTN as a protein secreted by CPC and enriched in their exosomal fraction. Purpose We sought to determine whether Exo-CPC can induce proliferation of CM and to explore the role of exosomal POSTN in inducing reentry of CM into the cell cycle. Methods Exo were isolated from CPC condioned medium by density gradient ultracentrifugation. Fractions were analyzed by Western blotting for the presence of POSTN as well as specific Exo markers (TSG101, CD9). POSTN-depleted Exo (ExoCPC_SiPOSTN) were obtained by transfecting CPC with specific siRNA. Active DNA synthesis was assessed on primary cell culture of rat neonatal CM by EdU incorporation. H9C2 cardiomyocytic cells were used to assess by real-time RT-PCR the expression of downstream genes Hippo/Yes-associated protein (YAP) signaling pathway. Results Western blotting analysis allowed to specifically determining the presence of Exo markers and POSTN in the different fractions of secreted vesicles. Smaller fractions (f1-f3) have the highest amount of TSG101 and CD9 as well as POSTN, thus suggesting that CPC secrete POSTN associated with Exo. The silencing of POSTN in cells resulted in a 60% reduction of Exo-associated POSTN compared to naïve ExoCPC. ExoCPC but not ExoCPC_SiPOSTN, were able to increase phosporylation of AKT and ERK in H9C2 cells. YAP phosporylation and its degradation was decreased resulting in the activation of the downstream gene AurBKinase. By real-time PCR, AurBKinase expression was increased by 2.6 folds with ExoCPC and 1.5 folds with ExoCPC_SiPOSTN compared to cells not exposed to Exo. ExoCPC were able to increase 1.5 fold EdU incorporation in cardiac troponin-positive primary rat CM. ExoCPC_SiPSTN did not affect proliferation. Schematic figure Conclusion These results suggest that POSTN may promote cardiomyocyte proliferation through the direct activation of the AKT/ERK/Hippo-Yap pathway. Exosomes released by CPC are an important source of POSTN and may have a potential for promoting cardiac regeneration. Acknowledgement/Funding This work has been supported by The Swiss National Science Foundation under grant n° 310030_169194

scholarly journals Histone deacetylase 1 controls cardiomyocyte proliferation during embryonic heart development and cardiac regeneration in zebrafish

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009890
Author(s):  
Anja Bühler ◽  
Bernd M. Gahr ◽  
Deung-Dae Park ◽  
Alberto Bertozzi ◽  
Alena Boos ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Heart Development ◽  
Positional Cloning ◽  
Molecular Mechanisms ◽  
Cardiac Regeneration ◽  
Border Zone ◽  
Cardiomyocyte Proliferation ◽  
Histone Deacetylase 1

In contrast to mammals, the zebrafish maintains its cardiomyocyte proliferation capacity throughout adulthood. However, neither the molecular mechanisms that orchestrate the proliferation of cardiomyocytes during developmental heart growth nor in the context of regeneration in the adult are sufficiently defined yet. We identified in a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen the recessive, embryonic-lethal zebrafish mutant baldrian (bal), which shows severely impaired developmental heart growth due to diminished cardiomyocyte proliferation. By positional cloning, we identified a missense mutation in the zebrafish histone deacetylase 1 (hdac1) gene leading to severe protein instability and the loss of Hdac1 function in vivo. Hdac1 inhibition significantly reduces cardiomyocyte proliferation, indicating a role of Hdac1 during developmental heart growth in zebrafish. To evaluate whether developmental and regenerative Hdac1-associated mechanisms of cardiomyocyte proliferation are conserved, we analyzed regenerative cardiomyocyte proliferation after Hdac1 inhibition at the wound border zone in cryoinjured adult zebrafish hearts and we found that Hdac1 is also essential to orchestrate regenerative cardiomyocyte proliferation in the adult vertebrate heart. In summary, our findings suggest an important and conserved role of Histone deacetylase 1 (Hdac1) in developmental and adult regenerative cardiomyocyte proliferation in the vertebrate heart.

The skyrmion annihilations induced by local reversal of background field in skyrmion lattice

2022 ◽  
Author(s):  
Yang Li ◽  
Hua Pang
Keyword(s):  
Stable State ◽  
Topological Defects ◽  
Background Field ◽  
Information Storage ◽  
Uniform Field ◽  
Annihilation Process ◽  
Complex Process ◽  
Potential Applications

Abstract The understanding of the creation and annihilation dynamics of a magnetic skyrmion is significant due to its potential applications in information storage and spintronics. Although there have been extensive investigations on the annihilation of isolated skyrmion, topological annihilation in periodic skyrmion lattice is a more complex process. We report a micromagnetic simulation study about the annihilation process of a two-dimensional skyrmion triangular lattice triggered by a uniform field HREV of comparable size to the skyrmion, which is opposite to the direction of the background field, revealing two annihilation modes. When the HREV center is within the range of a skyrmion, the neighboring skyrmions annihilate in situ, while the center is between adjacent skyrmions, anti-skyrmion is induced in the interstitial region. Both mechanisms tend to experience the intermediate topological vortex or antivortex structure, and the spin system undergoes a long period of relaxation to reach a stable state after the topological charge is stabilized. Our results present a local annihilation scheme that is easy to achieve in a 2D skyrmion lattice and highlight the role of interaction between skyrmions in the transformation between different kinds of topological defects.

Growth of Boron Nanowires by Chemical Vapor Deposition

2007 ◽  
Vol 1017 ◽  
Author(s):  
Li Guo ◽  
Raj N. Singh
Keyword(s):  
Vapor Deposition ◽  
Chemical Vapor ◽  
Growth Mechanisms ◽  
Nano Structures ◽  
Gas Chemistry ◽  
Potential Applications ◽  
Vls Growth ◽  
Boron Nanowires

AbstractMotivated by the extensive research on carbon nanotubes (CNTs), boron and its related nano-structures have attracted increasing interests for potential applications in nanodevices and nanotechnologies due to their extraordinary properties. B-related nanostructures are successfully grown on various substrates in a CVD process. The boron nanowires have diameters around 50-200 nanometers and lengths up to a few microns. The gas chemistry is monitored by the in-situ mass-spectroscopy, which helps to identify reactive species in the process. Modified vapor-solid growths as well as VLS growth mechanisms are proposed for the growth of these nanostructures. The role of the catalysts in the synthesis is also discussed.

scholarly journals Muscle-Specific Deletion of Rictor Impairs Insulin-Stimulated Glucose Transport and Enhances Basal Glycogen Synthase Activity

2007 ◽  
Vol 28 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Anil Kumar ◽  
Thurl E. Harris ◽  
Susanna R. Keller ◽  
Kin M. Choi ◽  
Mark A. Magnuson ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transport ◽  
Knockout Mice ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Physiological Processes ◽  
Glycogen Synthase Activity ◽  
Specific Deletion

ABSTRACT Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity.

The emerging role of MEIS1 in cell proliferation and differentiation

2020 ◽  
Author(s):  
Mingzhu Jiang ◽  
Shuang Xu ◽  
Mi Bai ◽  
Aihua Zhang
Keyword(s):  
Cell Proliferation ◽  
Cell Fate ◽  
Integration Site ◽  
Leukemia Cells ◽  
Cell Fate Specification ◽  
Cardiomyocyte Proliferation ◽  
Proliferative Effect ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

Cell proliferation and differentiation are the foundation of reproduction and growth. Mistakes in these processes may affect cell survival, or cause cell cycle dysregulation, such as tumorigenesis, birth defects and degenerative diseases, or cell death. Myeloid ecotropic viral integration site 1 (MEIS1) was initially discovered in leukemic mice. Recent research identified MEIS1 as an important transcription factor that regulates cell proliferation and differentiation during cell fate commitment. MEIS1 has a pro-proliferative effect in leukemia cells; however, its overexpression in cardiomyocytes restrains neonatal and adult cardiomyocyte proliferation. Additionally, MEIS1 has carcinogenic or tumor suppressive effects in different neoplasms. Thus, this uncertainty suggests that MEIS1 has a unique function in cell proliferation and differentiation. In this review, we summarize the primary findings of MEIS1 in regulating cell proliferation and differentiation. Correlations between MEIS1 and cell fate specification might suggest MEIS1 as a therapeutic target for diseases.

P5388N-cadherin promotes cardiac regeneration by stabilizing beta-catenin

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y S Tseng ◽  
M Y You ◽  
Y C Hsu ◽  
K C Yang
Keyword(s):  
Cell Cycle ◽  
Proliferative Activity ◽  
Cardiac Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Regenerative Capacity ◽  
Cell Cycle Genes ◽  
Multiple Cell

Abstract Background Although the adult mammalian heart fails to regenerate after injury, it is known that newborn mice within a week have full cardiac regenerative capacity. The molecular determinants underlying the disparate regenerative capacity between neonatal and adult mice, however, remain incompletely understood. Exploiting RNA sequencing in isolated cardiomyocytes from neonatal and adult mouse heart, we identified Cdh2, which encodes the adherence junction protein N-cadherin, as a potential novel mediator of cardiac regeneration. Cdh2 expression levels were much higher in neonatal, compared with adult, cardiomyocytes and showed a strong positive correlation with that of multiple cell cycle genes. N-cadherin has been reported to be essential for embryonic cardiac development; its role in cardiac regeneration, however, remains unknown. Purpose To determine the role of Cdh2 (N-cadherin) in cardiac regeneration and to investigate the underlying molecular mechanisms. Methods Apical resection in postnatal day 1 mice was used as a cardiac regenerative model. The in vitro gain/loss-of function studies of Cdh2/N-cadherin was performed in postnatal day 1 neonatal mouse cardiomyocytes (P1CM) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM). N-cadherin inhibitor exherin was used to study the effects of N-cadherin in vivo. Results Comparing to sham-operated control, Cdh2 was significantly upregulated in mouse cardiac apex and border zone following apical resection, which was accompanied with increased cardiomyocyte proliferation activity. In vitro, knocking down Cdh2 or inhibition of N-cadherin activity with exherin in P1CM significantly reduced the proliferative activity of cardiomyocytes, whereas overexpression of Cdh2 markedly increased the proliferation of P1CM. In addition, forced expression of Cdh2 resulted in significant upregulation of multiple cell cycle genes, including Ccnd1 (Cyclin D1) and Pcna (proliferating cell nuclear antigen), in P1CM. In vivo inhibition of N-cadherin in P1 neonatal mice with exherin following apical resection impaired cardiac regeneration and increased scar formation (Figure). Knocking down CDH2 in human iPSC-CMs significantly reduced the proliferative activity and the expression levels of cell cycle gene CCND1 in iPSC-CMs. Mechanistically, we demonstrated that the pro-mitotic effects of N-cadherin in cardiomyocytes were mediated, at least partially, by stabilizing β-catenin, a pro-mitotic transcription factor, through direct interaction with its cytoplasmic domain and/or inactivation of GSK3β, a critical component of β-catenin destruction complex. N-Cad blocker impairs heart regeneration Conclusion Our study uncovered a previously unrecognized role of Cdh2 (N-cadherin) in cardiomyocyte proliferation and cardiac regeneration. Enhancing cardiac expression or activity of N-cadherin, therefore, could be a potential novel therapeutic approach to promote cardiac regeneration and restore cardiac function in adult heart following injury.

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