scholarly journals Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration

Circulation ◽  
2020 ◽  
Vol 141 (15) ◽  
pp. 1249-1265 ◽  
Author(s):  
Ajit Magadum ◽  
Neha Singh ◽  
Ann Anu Kurian ◽  
Irsa Munir ◽  
Talha Mehmood ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cell Cycle ◽  
Pyruvate Kinase ◽  
Heart Development ◽  
Cardiac Development ◽  
Therapeutic Potential ◽  
Cardiac Regeneration ◽  
Chronic Myocardial Infarction ◽  
Term Survival

Background: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown. Methods: We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice. Results: Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. Conclusions: We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.

scholarly journals Hypoxia-induced myocardial regeneration

2017 ◽  
Vol 123 (6) ◽  
pp. 1676-1681 ◽  
Author(s):  
Wataru Kimura ◽  
Yuji Nakada ◽  
Hesham A. Sadek
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Systolic Heart Failure ◽  
Cardiac Regeneration ◽  
Oxygen Metabolism ◽  
Functional Improvement ◽  
Cardiomyocyte Proliferation ◽  
Mammalian Heart ◽  
Cell Cycle Reentry ◽  
And Oxidative Stress

The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration.

Role of D-type cyclins in heart development and disease

2012 ◽  
Vol 90 (9) ◽  
pp. 1197-1207 ◽  
Author(s):  
Adam Hotchkiss ◽  
Jessica Robinson ◽  
Jessica MacLean ◽  
Tiam Feridooni ◽  
Karim Wafa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Heart Development ◽  
Cardiac Development ◽  
Perinatal Period ◽  
Cell Cycle Regulators ◽  
Adult Heart ◽  
Signalling Molecules ◽  
Adult Cardiomyocytes ◽  
Catalytically Active ◽  
Permanent Cell

A defining feature of embryonic cardiomyocytes is their relatively high rates of proliferation. A gradual reduction in proliferative capacity throughout development culminates in permanent cell cycle exit by the vast majority of cardiomyocytes around the perinatal period. Accordingly, the adult heart has severely limited capacity for regeneration in response to injury or disease. The D-type cyclins (cyclin D1, D2, and D3) along with their catalytically active partners, the cyclin dependent kinases, are positive cell cycle regulators that play important roles in regulating proliferation of cardiomyocytes during normal heart development. While expression of D-type cyclins is generally low in the adult heart, expression levels are augmented in association with cardiac hypertrophy, but are uncoupled from myocyte cell division. Accordingly, re-activation of D-type cyclin expression in the adult heart has been implicated in pathophysiological processes via mechanisms distinct from those that drive proliferation during cardiac development. Growth factors and other exogenous agents regulate D-type cyclin production and activity in embryonic and adult cardiomyocytes. Understanding differences in the precise intracellular mediators downstream from these signalling molecules in embryonic versus adult cardiomyocytes could prove valuable for designing strategies to reactivate the cell cycle in cardiomyocytes in the setting of cardiovascular disease in the adult heart.

scholarly journals Molecular atlas of postnatal mouse heart development

2018 ◽  
Author(s):  
Virpi Talman ◽  
Jaakko Teppo ◽  
Päivi Pöhö ◽  
Parisa Movahedi ◽  
Anu Vaikkinen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Heart Development ◽  
Molecular Mechanisms ◽  
Mevalonate Pathway ◽  
Cardiac Regeneration ◽  
Neonatal Rat ◽  
Acid Oxidation ◽  
Mouse Heart ◽  
Tissue Samples ◽  
Combining Data

AbstractRationaleMammals lose the ability to regenerate their hearts within one week after birth. During this regenerative window, cardiac energy metabolism shifts from glycolysis to fatty acid oxidation, and recent evidence suggests that metabolism may participate in controlling cardiomyocyte cell cycle. However, the molecular mechanisms mediating the loss of postnatal cardiac regeneration are not fully understood.ObjectiveThis study aims at providing an integrated resource of mRNA, protein and metabolite changes in the neonatal heart to identify metabolism-related mechanisms associated with the postnatal loss of regenerative capacity.Methods and ResultsMouse ventricular tissue samples taken on postnatal days 1, 4, 9 and 23 (P01, P04, P09 and P23, respectively) were analyzed with RNA sequencing (RNAseq) and global proteomics and metabolomics. Differential expression was observed for 8547 mRNAs and for 1199 of the 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Gene ontology analysis, KEGG pathway analysis and fuzzy c-means clustering were used to identify biological processes and metabolic pathways either up- or downregulated on all three levels. Among these were branched chain amino acid degradation (upregulated at P23) and production of free saturated and monounsaturated medium- to long-chain fatty acids (upregulated at P04 and P09; downregulated at P23). Moreover, the HMG-CoA synthase (HMGCS)-mediated mevalonate pathway and ketogenesis were transiently activated. Pharmacological inhibition of HMGCS in primary neonatal rat ventricular cardiomyocytes reduced the percentage of BrdU+ cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating cardiomyocyte cell cycle.ConclusionsThis is the first systems-level resource combining data from genome-wide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses of the mouse heart throughout the early postnatal period. This integrated multi-level data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies.

Abstract 110: Human-Induced Pluripotent Stem Cell Derived Exosomal Protein Induce Cardiac Regeneration

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Ajit Magadum ◽  
Vandana Mallaredy ◽  
Grace Grace ◽  
Chunlin Wang ◽  
Rajika Roy ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cardiac Function ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Regeneration ◽  
Specific Protein ◽  
Post Injury ◽  
Proteomic Approach ◽  
Permanent Loss ◽  
Induced Pluripotent

Introduction: Cardiovascular diseases are the leading causes of death worldwide. After myocardial infarction (MI), there is a permanent loss of cardiomyocytes (CMs), and as the mammalian heart has limited regenerative capacity, it leads to Heart Failure. Recent studies from zebrafish and 1-day old mice showed that they could regenerate their heart through inducing existing CM proliferation. Attempts have been made to transiently reconstitute embryonic signaling in adult hearts, including overexpression of cell cycle activating genes with limited success. iPSC-derived extracellular vesicles (EV)/exosomes have been shown to improve cardiac function and some degree of CM renewal. However, the iPSC-EVs-mediated cardiac regeneration mechanism remains unclear and largely pertains to microRNAs and other RNAs, with a little elucidation of the role of iPSC-exosome proteins. Hypothesis: The myocardial delivery of iPSC-EV-specific protein improves cardiac function and remodeling post-MI by activating pro-proliferative and anti-oxidative stress molecular pathways. Methods and Results: Our preliminary studies showed that hiPSC-EVs induced the CM cell cycle in mice post-MI, and by employing a proteomic approach, we found a novel protein exclusively expressed in iPSC-EVs. The overexpression of hiPSC-EV enriched protein in the form of modRNA (modified mRNA) induced a robust CM cell cycle in rat neonatal CMs and in adult hearts post-MI. This increase in the CMs cell cycle by the modRNA was associated with reduced scar size, improved cardiac function (%EF 49.76 ± 5.8 vs. 27.47 ± 6.9 (control, Luc modRNA), respectively), and mice survival 28 days post-MI. Furthermore, using the siRNA and modRNA (inhibition and over-expression) approach, we found that the protein-induced Yap1-β-catenin molecular pathway stimulates CM proliferation. Furthermore, the overexpression protein post-MI inhibited the CM apoptosis (TUNEL + CMs, 1.3% ± 0.1 vs. 2.1% ± 0.11 (control)) by reducing oxidative stress and DNA damage response. Conclusion: The myocardial injection of iPSC-EV specific protein through a highly therapeutic modRNA tool improve cardiac function by inducing CMs proliferation, inhibiting oxidative stress, and reactivating cardiac regeneration post-injury.

scholarly journals Approaches to augment vascularisation and regeneration of the adult heart via the reactivated epicardium

2017 ◽  
Vol 2016 (4) ◽  
Author(s):  
Owen J Duffey ◽  
Nicola Smart
Keyword(s):  
Myocardial Infarction ◽  
Regenerative Medicine ◽  
De Novo ◽  
Cardiac Development ◽  
Survival Rates ◽  
Cardiac Regeneration ◽  
Developmental Processes ◽  
Paracrine Signalling ◽  
Important Regulator ◽  
Insight Into

Survival rates following myocardial infarction have increased in recent years but current treatments for post-infarction recovery are inadequate and cannot induce regeneration of damaged hearts. Regenerative medicine could provide disease-reversing treatments by harnessing modern concepts in cell and developmental biology. A recently-established paradigm in regenerative medicine is that regeneration of a tissue can be achieved by reactivation of the coordinated developmental processes that originally formed the tissue. In the heart, the epicardium has emerged as an important regulator of cardiac development and reactivation of epicardial developmental processes may provide a means to enable cardiac regeneration. Indeed, in adult mouse hearts, treatment with thymosin β4 and other drug-like molecules reactivates the epicardium and improves outcomes after myocardial infarction by inducing regenerative paracrine signalling, neovascularisation and de novo cardiomyocyte production. However, there are considerable limitations to current methods of epicardial reactivation that prevent direct translation into clinical practice. Here, we describe the rationale for targeting the epicardium and the successes and limitations of this approach. We consider how several recent advances in epicardial biology could be used to overcome these limitations. These advances include insight into epicardial signalling and heterogeneity, epicardial modulation of inflammation and epicardial remodelling of extracellular matrix. 

scholarly journals miRNA in cardiac development and regeneration

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhaohui Ouyang ◽  
Ke Wei
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Development ◽  
Heart Function ◽  
Cardiac Regeneration ◽  
Biological Processes ◽  
Cardiomyocyte Proliferation ◽  
Delivery Methods ◽  
New Strategy ◽  
Improve Heart Function ◽  
Multiple Species

AbstractIschemic heart disease is one of the main causes of morbidity and mortality in the world. In adult mammalian hearts, most cardiomyocytes are terminally differentiated and have extremely limited capacity of proliferation, making it impossible to regenerate the heart after injuries such as myocardial infarction. MicroRNAs (miRNAs), a class of non-coding single-stranded RNA, which are involved in mRNA silencing and the regulation of post-transcriptional gene expression, have been shown to play a crucial role in cardiac development and cardiomyocyte proliferation. Muscle specific miRNAs such as miR-1 are key regulators of cardiomyocyte maturation and growth, while miR-199-3p and other miRNAs display potent activity to induce proliferation of cardiomyocytes. Given their small size and relative pleiotropic effects, miRNAs have gained significant attraction as promising therapeutic targets or tools in cardiac regeneration. Increasing number of studies demonstrated that overexpression or inhibition of specific miRNAs could induce cardiomyocyte proliferation and cardiac regeneration. Some common targets of pro-proliferation miRNAs, such as the Hippo-Yap signaling pathway, were identified in multiple species, highlighting the power of miRNAs as probes to dissect core regulators of biological processes. A number of miRNAs have been shown to improve heart function after myocardial infarction in mice, and one trial in swine also demonstrated promising outcomes. However, technical difficulties, especially in delivery methods, and adverse effects, such as uncontrolled proliferation, remain. In this review, we summarize the recent progress in miRNA research in cardiac development and regeneration, examine the mechanisms of miRNA regulating cardiomyocyte proliferation, and discuss its potential as a new strategy for cardiac regeneration therapy.

Abstract 23: Overexpression Of Tbx20 In Adult Cardiomyocytes Promotes Cardiomyocyte Proliferation And Improves Cardiac Function Post Myocardial Infarction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Fu-li Xiang ◽  
Katherine Yutzey
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Cardiac Function ◽  
Heart Development ◽  
Weight Ratio ◽  
Negative Regulator ◽  
Proliferation Markers ◽  
Post Surgery ◽  
Adult Cardiomyocytes ◽  
Scar Size

Background: Adult mammalian cardiomyocytes (CM) have the potential to proliferate, but this is not sufficient to compensate for the massive loss of functional CMs after myocardial infarction (MI), which remains a leading cause of death in the US. During embryonic heart development, the transcription factor Tbx20 is required for CM proliferation, and Tbx20 overexpression promotes fetal characteristics in adult CMs when initiated before birth in mice. We hypothesize that Tbx20 overexpression (Tbx20OE), when induced in adult CMs after injury, improves cardiac function and repair via dedifferentiation of CMs, thus promoting cell cycle re-entry and repair in mice post-MI. Methods and Results: αMHCMerCreMer (STG) and the inducible cardiomyocyte-specific Tbx20 transgenic (αMHCMerCreMer/CAG-CAT-Tbx20, DTG) mice were subjected to MI or sham surgeries. Tbx20OE was induced 3 days post-surgery via tamoxifen to specifically target cardiac repair post-MI. In sham-operated mice, no difference in cardiac function or morphology was observed between DTG and STG groups. However, more proliferating CMs as labeled by Ki67 were found in DTG sham myocardium compared to STG. Expression of cyclin D1, E1 (cell cycle markers) and IGF1 mRNA was increased, while p21 (cell cycle inhibitor) and Meis1 (negative regulator of proliferation) were decreased, in DTG sham hearts compared to STG controls. In mice subjected to MI, cardiac function, as measured by echocardiography, was significantly improved, and the infarct scar size was smaller (58.1% vs 38.3%) in the DTG group compared to STG controls 2 and 4 weeks post-MI. Myocardial hypertrophy determined by heart to body weight ratio and myocyte diameter was also significantly reduced in DTG heart compared to STG 4 weeks post-MI. Thus, induction of Tbx20OE post-MI injury leads to improved cardiac performance, decreased scar size, and decreased maladaptive cardiac remodeling. Ongoing studies will determine if proliferation indices (Ki67, pHH3, aurora kinase B) and cytokinesis of CM post-MI are increased in myocardium and isolated adult cardiomyocytes with Tbx20OE. Conclusions: Tbx20OE in adult CM activates cell proliferation markers and also improves cardiac function and repair in mice when induced post-MI.

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.

Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction

2017 ◽  
Vol 131 (24) ◽  
pp. 2919-2932 ◽  
Author(s):  
Dezhong Yang ◽  
Wenbin Fu ◽  
Liangpeng Li ◽  
Xuewei Xia ◽  
Qiao Liao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Regeneration ◽  
Border Zone ◽  
Cardiomyocyte Proliferation ◽  
Great Loss ◽  
Wnt Proteins ◽  
Phosphohistone H3

After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson’s trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU+ cardiomyocytes. Meanwhile, CGX1321 increased Ki67+ and phosphohistone H3 (PH3+) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1. CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway.

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