Abstract 10: Cardiac-specific Yap Activation Improve Cardiac Function And Survival In An Experimental Murine Mi Model

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Zhiqiang Lin ◽  
Alexander von Gise ◽  
Pingzhu Zhou ◽  
Qing Ma ◽  
Jinghai Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Heart Function ◽  
Expression System ◽  
Gene Expression Signature ◽  
Cell Cycle Gene ◽  
Mouse Heart ◽  
Hippo Signaling ◽  
Cardiomyocyte Proliferation

Background: Yes-Associated Protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation. We hypothesized that YAP activation after myocardial infarction would preserve cardiac function and improve survival. Methods and Results: In this study, we used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the adult murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated cell cycle gene expression, activated of components of the inflammatory response, and promoted a less mature cardiac gene expression signature. Conclusions: Cardiac specific YAP activation after MI mitigated myocardial injury, improved cardiac function, and enhanced survival. These findings suggest that therapeutic activation of YAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI.

Abstract 16788: Delivery of Pluripotent Stem Cell Specific Microrna-294 Induces Cardiomyocyte Proliferation Augmenting Cardiac Function After Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Mohsin Khan ◽  
Suresh K Verma ◽  
Venkata N Garikipati ◽  
Jibin Zhou ◽  
Cynthia Benedict ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Stem Cell ◽  
Cardiac Function ◽  
Heart Function ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
Aurora B ◽  
Mrna Levels ◽  
Cardiomyocyte Proliferation

Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied. Objective: To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction. Methods and Results: miR expression analysis was carried out in the heart during development to determine levels of miR-294. Elevated level of miR-294 was observed in the prenatal heart confirmed by qRT-PCR. In contrast, miR-294 expression is lost in the neonates and adult mice. To further assess the effect of miR-294, neonatal ventricular cardiomyocytes (NRVMs) were treated with miR-294 mimic to determine the effect on proliferation and cell cycle. Elevated mRNA levels of cyclins A2 and E1 together with CDK2 was observed in NRVMs treated with 25nM mimic for miR-294. Increased expression of p-histone 3, PCNA (S-phase), Aurora B kinase (G2/M) and Ki67 was confirmed by immunocytochemistry in NRVMs after miR-294 treatment compared to control cells. Intramyocardial administration of miR-294 was carried out in mice at the time of myocardial infarction to determine whether miR-294 delivery increases cardiomyocyte proliferation and survival in response to injury. Enhance cardiac function was observed in mice receiving miR-294 3 weeks after myocardial infarction. Concurrently, increase myocyte proliferation was observed in the heart after miR-294 treatment as analyzed by BrdU uptake, PCNA and Aurora B expression by immunostaining. Conclusion: Ectopic expression of miR-294 recapitulates embryonic signaling and enhances cardiomyocyte ability to proliferate and reenter the cell cycle leading to augmented cardiac function in mice after myocardial infarction.

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.)

Abstract 12739: Microrna-294 Modulates Cardiomyocyte Proliferation Following Myocardial Infarction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Mohsin Khan ◽  
Emily Nickoloff ◽  
Jennifer Johnson ◽  
Suresh K Verma ◽  
Venkata N Garikipati ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Cardiac Function ◽  
Heart Function ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
Aurora B ◽  
Mrna Levels ◽  
Cardiomyocyte Proliferation ◽  
Histone 3

Rationale: Embryonic heart is characteristic of rapidly dividing cardiomyocytes that give rise to sufficient numbers required to build a working myocardium. In contrast, cardiomyocytes retain some proliferative capacity in the neonates but lose most of it in adulthood. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs regulating the unique cell cycle of ESCs and their characteristic pluripotency. Nevertheless, expression of miR-294, a member of the ESCC miRs is lost during developmental transitions from the ESCs to mature cells. Effect of miR-294 to induce cardiac proliferation and heart function has not been previously studied. Objective: To determine whether miR-294 drives cardiomyocyte cell cycle reentry leading to augmentation of cardiac function after myocardial infarction. Methods and Results: miR expression analysis in the heart during development revealed elevated levels of miR-294 in the prenatal stages while the expression was lost in the neonates and adults as confirmed by qRT-PCR. Neonatal ventricular cardiomyocytes (NRVMs) were treated with miR-294 mimic to determine the effect on proliferation and cell cycle. Elevated mRNA levels of cyclins A2, E1, CDK2 together with c-myc, E2F1 and E2F3 was observed in NRVMs treated with 25nM mimic for miR-294. Additionally, miR-294 treated NRVMs showed in AKT phosphorylation along with enhanced protein levels of cyclin D1 and E2F1. Increased expression of p-histone 3, Ki67 and Aurora B kinase (G2/M) was confirmed by immunocytochemistry in NRVMs after miR-294 treatment compared to control cells. Administration of miR-294 in mice subjected to myocardial infarction demonstrated augmentation of cardiac function in mice receiving miR-294 8 weeks after injury. Increase myocyte proliferation was observed in the heart after miR-294 treatment as analyzed by BrdU uptake, p-Histone 3 and Aurora B expression by immunostaining. Concurrently, a decrease in infarct size along with decreased apoptosis was observed in the miR-294 hearts compared to the control. Conclusion: Ectopic expression of miR-294 recapitulates embryonic signaling and enhances cardiomyocyte ability to proliferate and reenter the cell cycle leading to augmented cardiac function in mice after myocardial infarction.

scholarly journals Mesenchymal stem cells with overexpression of Angiotensin-converting enzyme-2 improved the microenvironment and cardiac function in a rat model of myocardial infarction

2020 ◽  
Author(s):  
Chao Liu ◽  
Yue Fan ◽  
Hong-Yi Zhu ◽  
Lu zhou ◽  
Yu Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Angiotensin Converting Enzyme ◽  
Cardiac Function ◽  
Heart Function ◽  
Tube Formation ◽  
Border Zone ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

AbstractBackgroundAngiotensin-converting enzyme-2 (ACE2) overexpression improves left ventricular remodeling and function in diabetic cardiomyopathy; however, the effect of ACE2-overexpressed mesenchymal stem cells (MSCs) on myocardial infarction (MI) remains unexplored. This study aimed to investigate the effect of ACE2-overexpression on the function of MSCs and the therapeutic efficacy of MSCs for MI.MethodsMSCs were transfected with Ace2 gene using lentivirus, and then transplanted into the border zone of ischemic heart. The renin-angiotensin system (RAS) expression, nitric oxide synthase (NOS) expression, paracrine factors, anti-hypoxia ability, tube formation of MSCs, and heart function were determined.ResultsMSCs expressed little ACE2. ACE2-overexpression decreased the expression of AT1 and VEGF apparently, up-regulated the paracrine of HGF, and increased the synthesis of Angiotensin 1-7 in vitro. ACE2-overexpressed MSCs showed a cytoprotective effect on cardiomyocyte, and an interesting tube formation ability, decreased the heart fibrosis and infarct size, and improved the heart function.ConclusionTherapies employing MSCs with ACE2 overexpression may represent an effective treatment for improving the myocardium microenvironment and the cardiac function after MI.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to oesophageal adenocarcinoma

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
Molecular Events ◽  
Common Causes ◽  
A Cell

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

2020 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D. Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

scholarly journals Cyclin D2 rescues size and function of GATA4 haplo-insufficient hearts

2012 ◽  
Vol 303 (8) ◽  
pp. H1057-H1066 ◽  
Author(s):  
Abir Yamak ◽  
Rana Temsah ◽  
Wael Maharsy ◽  
Sophie Caron ◽  
Pierre Paradis ◽  
...  
Keyword(s):  
Heart Function ◽  
Vital Role ◽  
Cell Cycle Gene ◽  
Cardiomyocyte Proliferation ◽  
Growth And Survival ◽  
Cardiac Phenotype ◽  
A Cell ◽  
Cell Growth And Differentiation ◽  
And Function ◽  
Cardiomyocyte Survival

Transcription factor GATA4 is a key regulator of cardiomyocyte growth, and differentiation and 50% reduction in GATA4 levels results in hypoplastic hearts. Search for GATA4 targets/effectors revealed cyclin D2 (CD2), a member of the D-type cyclins (D1, D2, and D3) that play a vital role in cell growth and differentiation as a direct transcriptional target and a mediator of GATA4 growth in postnatal cardiomyocytes. GATA4 associates with the CD2 promoter in cardiomyocytes and is sufficient to induce endogenous CD2 transcription and to dose-dependently activate the CD2 promoter in heterologous cells. Cardiomyocyte-specific overexpression of CD2 results in enhanced postnatal cardiac growth because of increased cardiomyocyte proliferation. When these transgenic mice are crossed with Gata4 heterozygote mice, they rescue the hypoplastic cardiac phenotype of Gata4+/− mice and enhance cardiomyocyte survival and heart function. The data uncover a role for CD2 in the postnatal heart as an effector of GATA4 in myocyte growth and survival. The finding that postnatal upregulation of a cell-cycle gene in GATA4 haplo-insufficient hearts may be protective opens new avenues for maintaining or restoring cardiac function in GATA4-dependent cardiac disease.

scholarly journals Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart

2013 ◽  
Vol 5 (2) ◽  
pp. 191-209 ◽  
Author(s):  
Konstantinos Malliaras ◽  
Yiqiang Zhang ◽  
Jeffrey Seinfeld ◽  
Giselle Galang ◽  
Eleni Tseliou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Progenitor Cell ◽  
Adult Mouse ◽  
Mouse Heart ◽  
Cardiomyocyte Proliferation ◽  
Cell Recruitment

scholarly journals Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

2016 ◽  
Vol 213 (7) ◽  
pp. 1353-1374 ◽  
Author(s):  
Anta Ngkelo ◽  
Adèle Richart ◽  
Jonathan A. Kirk ◽  
Philippe Bonnin ◽  
Jose Vilar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mast Cells ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Troponin I ◽  
Heart Function ◽  
Ischemic Disease ◽  
Cardiomyocyte Contractility ◽  
The Impact

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators.

Abstract 272: RBPJ Controls the Angiogenic Response of Mouse Adult Cardiomyocytes

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ramon Diaz Trelles ◽  
Maria Cecilia Scimia ◽  
Pilar Ruiz Lozano ◽  
Mark Mercola
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Target Genes ◽  
Notch Pathway ◽  
Oxygen Demand ◽  
Angiogenic Factors ◽  
Angiogenic Factor ◽  
Angiogenic Response ◽  
Adult Cardiomyocytes

Cardiac microvasculature density is critical for a correct cardiac function under normal and stress conditions. We found that the transcription factor RBPJ, downstream of the Notch signalling, can regulate angiogenic factors gene expression by repression (normal homeostasis) or activation (stress) and also by modulating the hypoxia induced angiogenic response. Accordingly, in normal conditions cardiomyocyte specific RBPJ KO adult mice hearts show a denser microvasculature. Isolated mouse adult cardiomyocytes show increased gene expression and promoter hyperacetylation and hypermethylation of angiogenic factors and Notch target genes (like HES1). Stress induced by myocardial infarction (MI) or cardiac overload (TAC) activate an angiogenic response to compensate the increased oxygen demand. Notch pathway is activated and RBPJ accumulated in the nucleus after MI and TAC. After TAC, deletion of RBPJ did not block hypertrophy induction, but prevented the increase in angiogenic factor production and microvessel density that normally occurs in response to increased workload. Remarkably, the KO preserved cardiac function and reduced cell death and fibrosis after myocardial infarction. Thus, RBPJ acts in cardiomyocytes as a master factor orchestrating homeostatic and disease-induced angiogenesis, and modulating RBPJ protects against ischemic injury.

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