Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA...

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Immunology

Background:

• LMNA-related dilated cardiomyopathy (LMNA-DCM) is a severe heart condition with high mortality due to poorly understood molecular mechanisms.
• Current treatment options for LMNA-DCM are limited, necessitating research into disease drivers.

Purpose of the Study:

• To comprehensively investigate the molecular mechanisms and identify key drivers of LMNA-DCM progression.
• To elucidate the role of DNA damage, innate immunity, and cell-cell communication in LMNA-DCM pathogenesis.

Main Methods:

• Utilized an inducible, cardiomyocyte-specific lamin A/C depletion mouse model.
• Conducted integrated bulk and single-nucleus RNA sequencing across disease progression.
• Developed a refined analysis pipeline to identify early misregulated genes.

Main Results:

• Identified 496 genes misregulated early in LMNA-DCM, driven by cardiomyocyte subpopulations.
• Observed increased DNA damage in cardiomyocytes correlating with reduced lamin A levels.
• Found evidence of cytosolic pattern recognition pathway activation and immune cell infiltration, alongside altered cardiac fibroblast gene expression.

Conclusions:

• Nuclear damage in cardiomyocytes initiates DNA damage responses and innate immune activation, contributing to LMNA-DCM.
• Altered cell-cell communication between cardiomyocytes, fibroblasts, and immune cells, mediated by extracellular matrix changes, plays a critical role.
• Findings suggest a multi-faceted pathogenesis involving inflammation and transcriptional remodeling, offering potential therapeutic targets.