scholarly journals Reciprocal Transcriptional Regulation of Metabolic and Signaling Pathways Correlates With Disease Severity in Heart Failure

2011 ◽  
Vol 4 (5) ◽  
pp. 475-483 ◽  
Author(s):  
Andreas S. Barth ◽  
Ami Kumordzie ◽  
Constantine Frangakis ◽  
Kenneth B. Margulies ◽  
Thomas P. Cappola ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcriptional Regulation ◽  
Signaling Pathways ◽  
Disease Severity

scholarly journals Distinct remodeling pattern between pediatric and adult heart failure: a focus on Ca2+ signaling pathway at proteomic level

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Zhang ◽  
U Kuzmanov ◽  
S Urschel ◽  
F Wang ◽  
S Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Signaling Pathways ◽  
Myocardial Dysfunction ◽  
Heart Defects ◽  
Systolic Dysfunction ◽  
Cellular Growth ◽  
Reverse Remodeling ◽  
Funding Source ◽  
Course Of Illness ◽  
Reduced Ejection Fraction

Abstract Background Dilated cardiomyopathy (DCM) is among the most common causes leading to end-stage heart failure with reduced ejection fraction (HF-rEF) in adult and pediatric patients. Despite similar phenotypes characterized as systolic dysfunction and eccentric ventricular dilation, pediatric DCM are biologically distinct entities with age- and development-specific features in the heart. Though underlying mechanisms may vary between the two populations, it's largely unexplored with few studies conducted to date. Purpose HF-rEF typically results from impaired myocardial contractility, triggered by defective cellular Ca2+ handling and cytoskeletal remodeling. Hence, we aim to integrate clinical profile and experimental data from human explanted hearts: 1) to unravel the age-dependent disparate Ca2+ signaling pathways; and 2) to identify pediatric-specific HF signatures or potential cures for precision managements. Methods Non-ischemic failing hearts (n=6 adult and n=6 pediatric) were procured immediately after excision via Human Explanted Heart Program. Age-matched adult non-failing control hearts (NFC, n=6) were obtained from deceased donors without cardiovascular history, while pediatric NFC (n=6) were collected from children with congenital heart defects but no primary myocardial dysfunction constituting relatively reasonable controls. Myocardial metabolic and oxidative profile were evaluated spectrophotometrically, and tissue remodeling was assessed immunohistochemically. Global proteomics and phosphoproteomics were performed on a Q-Exactive mass spectrometer, followed by network biology pathway analyses. Expression of screened proteins and kinases was validated by gel electrophoresis. Apoptosis and cellular growth signaling pathways were also incorporated into analysis. Results Both HF groups had remarkably lower LVEF (26.6±10.7% in pediatric vs. 26.5±9.1% in adult DCM) while compared to the NFC (both ≥60%) respectively. Histologically, adult-DCM demonstrated significantly worse fibrosis than pediatric-DCM (p<0.01). It was consistent with excessive reactive oxygen species (ROS) production and perturbed anti-ROS defense noted in adult-DCM, indicative of possible reverse remodeling in the pediatric failing hearts with shorter course of illness till transplant. Mechanistically, NCX1 was elevated with SERCA2 decreased in adult-DCM versus adult-NFC (p<0.05), while both pediatric groups exhibited comparable levels. Reduced p-/t-phospholamban and p-/t-CaMK in adult-DCM, unlike in pediatric-DCM, also illustrated altered phosphorylation patterns. Moreover, GSK-3β and AMPK pathways were inhibited while AKT-473 was activated in adult-DCM. Conclusions Pediatric DCM exhibited less adverse remodeling partially mediated by divergent Ca2+ handling and downstream signaling pathways, illustrating the fundamental differences between adult and pediatric DCM. Our findings may provide a scientific basis for the development of specific therapies for pediatric DCM. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)

Maximum phonation time is related to disease severity in male chronic heart failure patients

2014 ◽  
Vol 174 (3) ◽  
pp. 727-728 ◽  
Author(s):  
Kazuhiro P. Izawa ◽  
Satoshi Watanabe ◽  
Shinobu Tochimoto ◽  
Koichiro Oka ◽  
Yuhei Otobe ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Disease Severity ◽  
Maximum Phonation Time ◽  
Heart Failure Patients

scholarly journals Transcriptional regulation of structural and functional adaptations in a developing adulthood myocardium

2020 ◽  
Author(s):  
Sini Sunny ◽  
Anil Kumar Challa ◽  
Joseph Barchue ◽  
Muralidharan T. Ramamurthy ◽  
David K Crossman ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Signaling Pathways ◽  
Redox Homeostasis ◽  
Progressive Decline ◽  
Functional Changes ◽  
Adult Mice ◽  
Cycle Growth ◽  
Myocardial Development ◽  
Transcriptional Changes ◽  
Structural Adaptations

AbstractThe development of the heart follows a synergic action of several signaling pathways during gestational, pre- & postnatal stages. The current study aimed to investigate whether the myocardium experiences transcriptional changes during the transition from post-natal to adult hood stages. Herein, we used C57/Bl6/J mice at 4 (28-days; post-natal/PN) and 20 weeks (adulthood/AH) of ages and employed the next generation RNAseq (NGS) to profile the transcriptome and echocardiography analysis to monitor the structural/functional changes in the heart. NGS-based RNA-seq revealed that 1215 genes were significantly upregulated and 2549 were down regulated in the AH versus PN hearts, indicating a significant transcriptional change during this transition. A synchronized cardiac transcriptional regulation through cell cycle, growth hormones, redox homeostasis and metabolic pathways was noticed in both PN and AH hearts. Echocardiography reveals significant structural and functional (i.e. systolic/diastolic) changes during the transition of PN to adult stage. Particularly, a progressive decline in ejection fraction (EF) and cardiac output was observed in AH hearts. These structural adaptations are in line with critical signaling pathways that drive the maturation of heart during AH. Overall, we have presented a comprehensive transcriptomic analysis along with structural-functional relationship during the myocardial development in adult mice.

Abstract 246: Acetylation of Vgll4 Regulates Hippo-yap Signaling and Postnatal Cardiac Growth

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhiqiang Lin ◽  
Haidong Guo ◽  
Sylvia Zohrabian ◽  
Yuan Cao ◽  
William T. Pu
Keyword(s):  
Heart Failure ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Binding Protein ◽  
Cardiac Regeneration ◽  
Cardiac Growth ◽  
Kinase Cascade

Binding of the transcription co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. Many signaling pathways, including the Hippo kinase cascade, converge to regulate YAP activity. However, less in known about the mechanisms that govern TEAD. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP’s mitogenic potency declines postnatally, when mammalian cardiomyocytes largely exit the cell cycle. Here, we show that VGLL4, a CM-enriched TEAD1 binding protein, inhibits CM proliferation by limiting its binding to YAP and by targeting TEAD1 for degradation. VGLL4 antagonism of TEAD1 was governed by its acetylation at K225. Overexpression of VGLL4-K225R, an acetylation-refractory mutant, enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis and heart failure. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates YAP-TEAD1 activity and restrains CM proliferation. These insights may enable more effective regulation of TEAD-YAP activity in applications ranging from cardiac regeneration to restraining cancer.

Abstract 12549: Circulating Irisin is a Novel Biomarker Providing Prognostic Information in Patients With Heart Failure With Reduced Ejection Fraction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shinsuke Hanatani ◽  
Yasuhiro Izumiya ◽  
Yuichi Kimura ◽  
Yoshiro Onoue ◽  
Satoshi Araki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Ejection Fraction ◽  
Disease Severity ◽  
Cardiovascular Events ◽  
Roc Analysis ◽  
Left Ventricular Ejection ◽  
Prognostic Information ◽  
Reduced Ejection Fraction ◽  
One Year

Introduction: Reduced skeletal muscle function link to poor prognosis in patients with chronic heart failure (HF). Irisin is a newly identified muscle-derived protein found in human serum. The gene expression of irisin precursor fibronectin domain containing protein 5 in skeletal muscle is associated with exercise tolerance in HF patients. Hypothesis: Irisin could be a useful biomarker for disease severity and future adverse cardiovascular events in patients with HF with reduced ejection fraction (HFrEF). Methods and results: We measured serum irisin levels in 84 patients with HFrEF. HFrEF was defined as left ventricular ejection fraction≦50% and meet the Framingham criteria of HF. Serum irisin concentrations were measured by ELISA. The endpoint of this study was a composite of total mortality, cardiovascular hospitalization and coronary revascularization. Serum irisin levels were negatively correlated with serum high sensitive troponin T levels (r=-0.24, p=0.048). Right heart catheterization revealed that serum irisin levels had significant negative correlation with pulmonary capillary wedge pressure (r=-0.23, p=0.044). In receiver operating characteristic (ROC) analysis, cut-off values of irisin and BNP for prediction of one-year events were 55.548 ng/mL and 324.8 pg/mL, respectively. Kaplan Meier curve demonstrated that the event-free rate was decreased in the low irisin (≦cut-off value) group (log-rank test p=0.024). The combination of low irisin and high BNP (≧cut-off value) identified patients with a significantly higher probability of adverse events (p=0.008). Multivariate Cox hazard analysis identified low levels of irisin (≦cut-off value) (hazard ratio [HR]: 3.08; 95% confidence interval [CI]: 1.31-7.21, p=0.01) and ischemic etiology (HR: 3.32; 95% CI: 1.50-7.35, p=0.003) as independent predictors of mortality and cardiovascular events. ROC analysis revealed that irisin achieved an area under the curve (AUC) of 0.67 for one-year events (p=0.031), and that the AUC increased when irisin was added to BNP level (alone: 0.64, BNP+irisin: 0.74). Conclusions: Irisin could be a useful biomarker for evaluating disease severity and providing incremental prognostic information in patients with HFrEF.

Identification of transcription factors MYC and C/EBPβ mediated regulatory networks in heart failure based on GEO dataset

2020 ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Hua Cao
Keyword(s):  
Heart Failure ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Regulatory Networks ◽  
Target Genes ◽  
Transcriptional Profiling ◽  
Insulin Signaling Pathway ◽  
Failing Heart

Abstract Background: Heart failure is one of leading cause of death worldwide. However, the transcriptional profiling of heart failure is unclear. Moreover, the signaling pathways and transcription factors involving the heart failure development also are largely unknown. Using published Gene Expression Omnibus (GEO) datasets, in the present study, we aim to comprehensively analyze the differentially expressed genes in failing heart tissues, and identified the critical signaling pathways and transcription factors involving heart failure development. Methods: The transcriptional profiling of heart failure was identified from previously published gene expression datasets deposited in GSE5406, GSE16499 and GSE68316. The enriched signaling pathways and transcription factors were analyzed using DAVID website and gene set enrichment analysis (GSEA) assay. The transcriptional networks were created by Cytoscape. Results: Compared with the normal heart tissues, 90 genes were particularly differentially expressed in failing heart tissues, and those genes were associated with multiple metabolism signaling pathways and insulin signaling pathway. Metabolism and insulin signaling pathway were both inactivated in failing heart tissues. Transcription factors MYC and C/EBPβ were both negatively associated with the expression profiling of failing heart tissues in GSEA assay. Moreover, compared with normal heart tissues, MYC and C/EBPβ were down regulated in failing heart tissues. Furthermore, MYC and C/EBPβ mediated downstream target genes were also decreased in failing heart tissues. MYC and C/EBPβ were positively correlated with each other. At last, we constructed MYC and C/EBPβ mediated regulatory networks in failing heart tissues, and identified the MYC and C/EBPβ target genes which had been reported involving the heart failure developmental progress. Conclusions: Our results suggested that metabolism pathways and insulin signaling pathway, transcription factors MYC and C/EBPβ played critical roles in heart failure developmental progress.

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