A directed network analysis of the cardiome identifies molecular pathways contributing to the development of HFpEF

Autor: Daniela Miranda-Silva, Adelino F. Leite-Moreira, Chantal Munts, Marc van Bilsen, Georg Summer, André P. Lourenço, Annika R. Kuhn, Stephane Heymans, Inês Falcão-Pires
Přispěvatelé: Cardiologie, Promovendi CD, Fysiologie, RS: Carim - H02 Cardiomyopathy, MUMC+: MA Med Staf Spec Cardiologie (9)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
EXPRESSION
Systems biology
Heart failure
Computational biology
MYC
030204 cardiovascular system & hematology
Biology
Ventricular Function
Left
Transcriptome
ACTIVATION
03 medical and health sciences
0302 clinical medicine
Complementary DNA
PPAR-ALPHA
Protein Interaction Mapping
Ventricular Dysfunction
Animals
Obesity
Protein Interaction Maps
Transcriptomics
Molecular Biology
Transcription factor
Gene
Gene Expression Profiling
Autophagy
Computational Biology
Stroke Volume
Metabolic syndrome
DYSFUNCTION
Rats
HYPERTROPHY
Disease Models
Animal
030104 developmental biology
PRESERVED EJECTION FRACTION
Mitochondrial metabolism
HEART-FAILURE
Disease Susceptibility
HYPOPHOSPHORYLATION
Cardiology and Cardiovascular Medicine
Heart failure with preserved ejection fraction
Function (biology)
Zdroj: Journal of Molecular and Cellular Cardiology, 144, 66-75
Journal of Molecular and Cellular Cardiology, 144, 66-75. ELSEVIER SCI LTD
ISSN: 0022-2828
Popis: Aims: The metabolic syndrome and associated comorbidities, like diabetes, hypertension and obesity, have been implicated in the development of heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms underlying the development of HFpEF remain to be elucidated. We developed a cardiome-directed network analysis and applied this to high throughput cardiac RNA-sequencing data from a well-established rat model of HFpEF, the obese and hypertensive ZSF1 rat. With this novel system biology approach, we explored the mechanisms underlying HFpEF.Methods and results: Unlike ZSF1-Lean, ZSF1-Obese and ZSF1-Obese rats fed with a high-fat diet (HFD) developed diastolic dysfunction and reduced exercise capacity. The number of differentially expressed genes amounted to 1591 and 1961 for the ZSF1-Obese vs. Lean and ZSF1-Obese+HFD vs. Lean comparison, respectively. For the cardiome-directed network analysis (CDNA) eleven biological processes related to cardiac disease were selected and used as input for the STRING protein-protein interaction database. The resulting STRING network comprised 3.460 genes and 186.653 edges. Subsequently differentially expressed genes were projected onto this network. The connectivity between the core processes within the network was assessed and important bottleneck and hub genes were identified based on their network topology.Classical gene enrichment analysis highlighted many processes related to mitochondrial oxidative metabolism. The CDNA indicated high interconnectivity between five core processes: endothelial function, inflammation, apoptosis/autophagy, sarcomere/cytoskeleton and extracellular matrix. The transcription factors Myc and Peroxisome Proliferator-Activated Receptor-alpha (Ppara) were identified as important bottlenecks in the overall network topology, with Ppara acting as important link between cardiac metabolism, inflammation and endothelial function.Conclusions: This study presents a novel systems biology approach, directly applicable to other cardiac disease related transcriptome data sets. The CDNA approach enabled the identification of critical processes and genes, including Myc and Ppara, that are putatively involved in the development of HFpEF.
Databáze: OpenAIRE
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