TY - JOUR
T1 - Gene expression networks in endothelial cells from failing human hearts
AU - Wirth, Luisa
AU - Erny, Elias
AU - Krane, Markus
AU - Lahm, Harald
AU - Hein, Lutz
AU - Gilsbach, Ralf
AU - Lother, Achim
PY - 2024/9/1
Y1 - 2024/9/1
N2 - 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.
AB - 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.
KW - endothelial cells
KW - heart
KW - heart failure
KW - transcription factor
KW - transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85202085387&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00425.2024
DO - 10.1152/ajpheart.00425.2024
M3 - Article
C2 - 39028282
AN - SCOPUS:85202085387
SN - 0363-6135
VL - 327
SP - H573-H581
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 3
ER -