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Gene Expression Analysis of Endothelial Cells Exposed to Shear Stress Using Multiple Parallel-plate Flow Chambers
Published on: October 21, 2018
Gene expression networks in endothelial cells from failing human hearts
Luisa Wirth1, Elias Erny1, Markus Krane2,3,4
1Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Insights
Researchers identified key gene networks and transcription factors, including CASZ1, ZNF523, and NFE2L1, that regulate angiogenesis in heart failure. This finding offers new insights beyond traditional signaling pathways.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Genomics
Background:
- Chronic heart failure involves adverse cardiac remodeling and cardiomyocyte hypertrophy.
- Adequate oxygen supply necessitates new capillary formation (angiogenesis).
- Impaired angiogenesis exacerbates heart failure progression.
Purpose of the Study:
- To identify angiogenesis-related gene networks in endothelial cells from failing human hearts.
- To pinpoint regulatory hub genes controlling angiogenesis in heart failure.
- To explore transcriptional regulation of angiogenesis beyond established pathways.
Main Methods:
- Isolation of left ventricular endothelial cells from heart failure patients and healthy donors.
- RNA sequencing and weighted gene coexpression network analysis.
- Validation of identified hub genes (CASZ1, ZNF523, NFE2L1) via knockdown experiments.
Main Results:
- Identified 26 gene clusters, with 9 significantly correlated with heart failure.
- Discovered CASZ1, ZNF523, and NFE2L1 as hub genes in an angiogenesis-related cluster.
- Knockdown of these transcription factors downregulated key angiogenesis genes (e.g., CD34).
Conclusions:
- CASZ1, ZNF523, and NFE2L1 are potential regulators of angiogenesis in failing human hearts.
- These findings expand understanding of transcriptional control of angiogenesis in heart failure.
- The study highlights novel targets for therapeutic intervention in heart failure.
Abstract:
Chronic heart failure is associated with adverse remodeling of the heart that is typically characterized by cardiomyocyte hypertrophy. This requires the formation of new capillaries to maintain oxygen supply. Insufficient angiogenesis promotes the transition from compensated hypertrophy into heart failure. The aim of this study was to identify angiogenesis-related gene networks and corresponding regulatory hubs in endothelial cells from failing human hearts. We isolated left ventricular endothelial cells from patients with advanced heart failure undergoing left ventricular assist device surgery (n = 15) and healthy organ donors (n = 2) and performed RNA sequencing. Subgroup analysis revealed no impact of comorbidities on gene expression. In a weighted gene coexpression network analysis, we found 26 gene clusters, of which 9 clusters showed a significant positive or negative correlation with the presence of heart failure. We identified the transcription factors CASZ1 (castor zinc finger 1), ZNF523 (zinc finger protein 523), and NFE2L1 (nuclear factor erythroid 2-related factor 1) as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, including CD34 and platelet-derived growth factor-β, confirming their regulatory function. In conclusion, we assessed gene networks in endothelial cells and identified transcription factors CASZ1, ZNF532, and NFE2L1 as potential regulators of angiogenesis in failing human hearts. Our study provides insights into the transcriptional regulation of angiogenesis beyond the classical vascular endothelial growth factor signaling pathway.NEW & NOTEWORTHY Gene coexpression network analysis defined 26 gene clusters expressed in endothelial cells from failing human hearts. Transcription factors CASZ1, ZNF523, and NFE2L1 were identified as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, confirming their regulatory function. This provides insights into the transcriptional regulation of angiogenesis in heart failure beyond classical signaling pathways.
