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.

Abstract 648: Heme-oxygenase-1 Gene Expression Ameliorates Cardiac Dysfunction Following Myocardial Infarction In C57 Mice By Recruitment Of Angiogenic Factors And Angiogenesis In C57 Mice

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
David Sacerdoti ◽  
Sumit R Monu ◽  
Paola Pesce ◽  
Stephen J Peterson ◽  
Komal Sodhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Heme Oxygenase ◽  
Angiogenic Factors ◽  
Heme Oxygenase 1 ◽  
Artery Ligation ◽  
Capillary Formation ◽  
Beneficial Effects ◽  
Angiogenic Proteins

Rational: Angiogenesis is essential in order to increase blood circulation in infarcted tissue of MI (Myocardial infarction). Increased Heme-Oxygenase (HO)-1 gene expression increases angiogenic proteins, e.g. VEGF, bFGF, EGF, angiopoietin and adiponectin. Objective: To investigate whether increased levels of HO-1, after the occurrence of a MI, improves angiogenesis and capillary formation in ischemic myocardium, thereby improving cardiac function. METHODS: Experimental MI was induced by LAD (Left anterior descending artery) ligation. C57BL6 mice were divided into 4 groups: Sham; MI; 5 days after MI treated with the HO-1 inducer, cobalt protoporphyrinIX (CoPP); and, CoPP in the presence of the HO activity inhibitor, Stannous Mesoporphyrin (SnMP). HO-1 downstream signaling proteins were determined including VEGF, CD31 and adiponectin. Echocardiography was performed weekly for 4 weeks after surgery. Results: 5 days after MI, CoPP treatment significantly increased VEGF (p<0.05 vs.MI), CD31 (p<0.05 vs.MI), and adiponectin levels (p<0.05 vs.MI). These findings were associated with a significant increase in capillary formation and blood flow in CoPP-treated animals (p<0.05 vs.MI). Echocardiography showed that left ventricle dilatation, measured as end diastolic area (EDA), was significantly reduced in CoPP- treated animals compared to MI groups (EDA: MI: 0.216±0.02cm2; MI+CoPP: 0.172±0.03 cm2; (-13%) p<0.01). This was associated with a significant decrease in apoptosis and fibrosis (P<0.05). These beneficial effects were reversed by SnMP administration. Conclusion: HO-1 improved cardiac function and enhanced angiogenesis via the recruitment of pro-angiogenic factors.

The Histone Deacetylase Inhibitor LAQ824 Maintains Normal Hematopoietic Progenitor cells (HPC) Associated with Induction of Notch Target Genes and Does Not Eliminate Leukemic HPC in Vitro.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1352-1352
Author(s):  
Kerstin Schwarz ◽  
Oliver Ottmann ◽  
Annette Romanski ◽  
Anja Vogel ◽  
Jeffrey W. Scott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Progenitor Cells ◽  
Gene Expression Analysis ◽  
Target Genes ◽  
Notch Pathway ◽  
Cycle Arrest ◽  
Cd34 Cells ◽  
20 Nm

Abstract Introduction: Histone deacetylase inhibitors (DACi) have shown promising antileukemic activity by overcoming the differentiation block and inducing apoptosis in AML blasts. Recent data demonstrating enhanced maintenance and functional capacity of normal, but also leukemic hematopoietic progenitor cells (HPC) by the selective class I DACi valproic acid (VPA) have raised concerns about VPA in AML therapy. As more potent pan-DACi have entered clinical trials, we analysed the impact of the hydroxamic acid LAQ824 on phenotype and function of normal and leukemic CD34+ HPC and studied LAQ824- induced gene expression in the most primitive CD34+CD38- population of normal HPC. Methods: Differentiation and proliferation of CD34+ cells of bone marrow of healthy donors and peripheral blood samples of newly diagnosed AML patients were evaluated after one week of culture in presence of SCF, FLT3 ligand, TPO, IL-3 +/− LAQ824. The effect of LAQ824 on gene expression profiles in normal CD34+CD38− cells was assessed in three independent cell samples following incubation with cytokines +/− LAQ824 for 48 hours using Affymetrix GeneChip Human Genome U133 Plus 2.0 and Gene Spring Software. Serial replating of murine Sca1+Lin- HPC was performed in the presence of SCF, G-CSF, GM-CSF, IL-3, IL-6 +/− LAQ824. Results: Treatment of murine Sca1+Lin- HPC with LAQ824 (10 nM) significantly augmented colony numbers (p&lt;0.01; n=3), and supported colony growth after four cycles of replating whereas no colonies developed in its absence beyond the second plating indicating preservation of functionally active multipotent progenitor cells. LAQ824 (10–20 nM) mediated acetylation of histone H3 in human normal and leukemic HPC. In normal HPC, LAQ824 (0–20 nM) lead to a dose-dependent increase in the proportion of CD34+ cells (20% w/o LAQ824 vs. 36% with LAQ824 20nM, p=0.07) and a significant reduction of CD14+ monocytes (18% vs. 3%, p= 0.02; n=3). The total number of CD34+ cells remained stable up to 10 nM and decreased at 20 nM. Gene expression analysis showed, that LAQ824 (20 nM) lead to an at least 3-fold up-regulation of 221 genes in all three HPC samples tested including HDAC11 and the cell cycle inhibitor p21waf1/cip1 known to be induced by most DACi in HPC. We identified several members of the notch pathway such as mastermind-like protein 2 (MAML2, a component of the active notch transcriptional complex) and notch target genes including the transcription factors HES1, HEY1 and HOXA10 and confirmed increase of protein levels by Western blotting. Reduced gene expression of mini-chromosome-maintenance (MCM) protein family members was observed which - in addition to up-regulation of p21 - has previously been associated with notch-mediated cell cycle arrest. To compare the effect of LAQ824 (20 nM) with VPA (150 ng/ml) on leukemic HPC, cells were cultured for one week with or w/o DACi. Of note, LAQ824 resulted in a 0.8-fold reduction of CD34+ leukemic HPC, while VPA expanded this population 2.2-fold compared with cytokine-treated controls (p=0.03; n=12). CFU numbers growing from CD34+ leukemic HPC in presence of LAQ824 did not differ significantly from controls (n=9). Conclusion: LAQ824 seems to diminish, but not eliminate normal as well as leukemic HPC as determined by phenotypic and functional in vitro analyses. Our gene expression analysis suggested an association with coactivator and target genes of the notch pathway and cell cycle arrest-inducing genes. In contrast to VPA, LAQ824 does not seem to support growth of leukemic HPC which may contribute to its more potent antileukemic effect.

Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates

2021 ◽  
Vol 13 (584) ◽  
pp. eabb0202
Author(s):  
Qingju Li ◽  
Yinchuan Xu ◽  
Kaiqi Lv ◽  
Yingchao Wang ◽  
Zhiwei Zhong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Extracellular Vesicles ◽  
Nonhuman Primates ◽  
Target Genes ◽  
Cardiac Fibroblasts ◽  
Vascular Density ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Stem cell–derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV–treated than N-sEV–treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and Mmp19 was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed Mmp19 and miR-486-5p abolished this effect. Mmp19 silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p–overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p–engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.

scholarly journals Assessment of cardiac function with the pressure-volume conductance system following myocardial infarction in mice

2007 ◽  
Vol 293 (5) ◽  
pp. H2870-H2877 ◽  
Author(s):  
Krystyna M. Shioura ◽  
David L. Geenen ◽  
Paul H. Goldspink
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Systolic Dysfunction ◽  
Cardiac Contractility ◽  
Loop Analysis ◽  
Significant Deterioration ◽  
Adult Mice ◽  
Matrix Gene

Myocardial infarction (MI) is a major cause of heart failure (HF) with the progressive worsening of cardiac performance due to structural and functional alterations. Therefore, we studied cardiac function in adult mice following MI using the Millar pressure-volume (P-V) conductance catheter system in vivo during the later phase of compensatory remodeling and decompensation to HF. We evaluated load-dependent and -independent parameters in control and 2-, 4-, 6-, and 10-wk post-MI mice and integrated changes in function with changes in gene expression. Our results indicated a significant deterioration of cardiac function in post-MI mice over time, reflected first by systolic dysfunction, followed by a transient improvement before further decline in both systolic and diastolic function. Associated with the function and adaptive remodeling were transient changes in fetal gene and extracellular matrix gene expression. However, undermining the compensatory remodeling response was a continual decline in cardiac contractility, which promoted the transition into failure. Our study provided a scheme of integrated cardiac function and gene expression changes occurring during the adaptive and maladaptive response of the heart independent of systemic vascular properties during the transition to HF following MI in mice. P-V loop analysis was used to quantitatively evaluate the gradual deterioration in cardiac function post-MI. P-V loop analysis was found to be an appropriate method for assessment of global cardiac function under varying load-dependent and -independent conditions in the murine model with many similarities to data obtained from larger animals and humans.

scholarly journals The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001334
Author(s):  
Miren Maicas ◽  
Ángela Jimeno-Martín ◽  
Andrea Millán-Trejo ◽  
Mark J. Alkema ◽  
Nuria Flames
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Cell Signalling ◽  
Notch Pathway ◽  
Receptor Activation ◽  
Notch Signalling ◽  
Notch Receptor ◽  
Specific Gene ◽  
Effector Genes

During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling.

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.

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.

Influence of long-term treatment of imidapril on mortality, cardiac function, and gene expression in congestive heart failure due to myocardial infarction

2004 ◽  
Vol 82 (12) ◽  
pp. 1118-1127 ◽  
Author(s):  
Bin Ren ◽  
Qiming Shao ◽  
Pallab K Ganguly ◽  
Paramjit S Tappia ◽  
Nobuakira Takeda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Congestive Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Function ◽  
Term Treatment ◽  
Cardiac Performance ◽  
Long Term Treatment

Although it is generally accepted that the efficacy of imidapril, an angiotensin-converting enzyme inhibitor, in congestive heart failure (CHF) is due to improvement of hemodynamic parameters, the significance of its effect on gene expression for sarcolemma (SL) and sarcoplasmic reticulum (SR) proteins has not been fully understood. In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ ATPase and Na+–Ca2+ exchanger as well as SR Ca2+ pump ATPase, Ca2+ release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction. Heart failure subsequent to myocardial infarction was induced by occluding the left coronary artery in rats, and treatment with imidapril (1 mg·kg–1·day–1) was started orally at the end of 3 weeks after surgery and continued for 37 weeks. The animals were assessed hemody nam ically and the heart and lung were examined morphologically. Some hearts were immediately frozen at –70 °C for the isolation of RNA as well as SL and SR membranes. The mortality of imidapril-treated animals due to heart failure was 31% whereas that of the untreated heart failure group was 64%. Imidapril treatment improved cardiac performance, attenuated cardiac remodeling, and reduced morphological changes in the heart and lung. The depressed SL Na+/K+ ATPase and increased SL Na+–Ca2+ exchange activities as well as reduced SR Ca2+ pump and SR Ca2+ release activities in the failing hearts were partially prevented by imidapril. Although changes in gene expression for SL Na+/K+ ATPase isoforms as well as Na+–Ca2+ exchanger and SR phospholamban were attenuated by treatments with imidapril, no alterations in mRNA levels for SR Ca2+ pump proteins and Ca2+ release channels were seen in the untreated or treated rats with heart failure. These results suggest that the beneficial effects of imidapril in CHF may be due to improvements in cardiac performance and changes in SL gene expression.Key words: sarcolemmal Na+/K+ ATPase, Na+–Ca2+ exchange, sarcoplasmic reticulum, heart failure, ACE inhibition.

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