RUNX1-driven endothelial-to-mesenchymal transition contributes to remodelling in LMNA cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Genetic Cardiology
• Molecular Mechanisms of Disease

Background:

• LMNA-related dilated cardiomyopathy (LMNA-DCM) is a progressive genetic heart disorder.
• Fibrotic remodeling in LMNA-DCM is poorly understood, despite its association with cardiomyocyte defects.

Purpose of the Study:

• To investigate the mechanisms driving fibrotic remodeling in LMNA-DCM.
• To identify endothelial cell transcriptional and epigenomic states associated with fibrosis.
• To explore RUNX1-mediated endothelial-to-mesenchymal transition (EndoMT) as a therapeutic target.

Main Methods:

• Spatial transcriptomics and single-nuclei multiomics on human LMNA-DCM hearts.
• Utilized patient-specific induced pluripotent stem cell-derived endothelial cells and cardiac organoids.
• Employed the LMNAH222P/H222P mouse model for in vivo studies.
• Investigated genetic and pharmacological RUNX1 inhibition.

Main Results:

• Identified endothelial EndoMT signatures in human LMNA-DCM hearts.
• LMNA deficiency induced endothelial dysfunction and RUNX1 activation.
• RUNX1 inhibition restored endothelial identity and normalized cardiac function in organoids and mice.
• Pharmacological RUNX1 inhibition reduced fibrosis and preserved cardiac function in a mouse model.

Conclusions:

• RUNX1-driven EndoMT is a central mechanism linking LMNA mutations to fibrosis in cardiomyopathy.
• Endothelial transcriptional reprogramming and RUNX1 signaling are potential therapeutic targets for fibrotic cardiomyopathy.