Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart

Abstract

Aim Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. Methods and Results We carried out a comprehensive meta-analysis of integrated single cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularisation. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1 and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularisation. Conclusion We present a high-resolution single cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development. Translational Perspective Myocardial infarction is the leading cause of heart failure, a condition with high morbidity and mortality. Vascular regeneration is vital to tissue survival and functional restoration while a comprehensive understanding of the underpinning mechanisms is lacking. We show that the meta-analysis of single cell RNA-sequencing data excels at deciphering multi-faceted vascular responses conserved between mouse and human following ischaemic injury. We envision that these data will inform future strategies and accelerate therapeutic development for promoting vascular regeneration in the ischaemic heart.

Identification and Validation of Hub Genes Related to Neutrophil Extracellular Traps-Mediated Cell Damage During Myocardial Infarction

“… 52 Li et al also found significantly elevated ZFP36 protein levels in ischemic human heart tissue and knockdown of ZFP36 in HCMECs using siRNA significantly inhibited cell proliferation. 53 Our analysis suggests that ZFP36 may be one of the targets of endothelial cell injury by NETs during MI and may be a promising novel target for the treatment of ischemic heart disease.…”

Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy

“…The VEGFB-iECs were not affected during pregnancy, and they were only increased by 4.3% in WT mice subjected to LAD ligation. Interestingly, recent analyses of transcriptomic changes in ischemic human hearts and in mice after MI [64][65][66][67] do not indicate significant upregulation of VEGFB-iEC marker transcripts. Thus, the unique ability of VEGF-B to expand the VEGFB-iEC population likely underlies the protective effects of VEGF-B in the ischemic heart.…”

Integrated analysis of single-cell RNA sequencing and bulk RNA data reveals gene regulatory networks and targets in dilated cardiomyopathy

“…Zhang et al reported that enhanced expression of ZFP36 in aortic endothelial cells might reduce vascular inflammation through direct binding to target cytokine mRNAs 36 . A meta-analysis of single-cell RNA sequencing targeting multiple species revealed that ZFP36 regulates human coronary artery endothelial cell proliferation in ischemic hearts and determined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vascular after myocardial infarction 37 . Our research indicates that CDKN1A, SAT1, and ZFP36 share overlapping upstream transcription factors, which are in fact members of the AP-1 family, playing an important role in regulating cellular proliferation, differentiation, and biological response processes 38 .…”