Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Systems Biology

Background:

• Pressure overload is a major cause of cardiac hypertrophy and subsequent heart failure.
• The precise molecular mechanisms driving the transition from compensated hypertrophy to decompensated heart failure remain incompletely understood.
• Understanding cardiomyocyte remodeling is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate the molecular trajectory of cardiomyocyte remodeling during pressure overload.
• To identify distinct gene programs associated with cardiac hypertrophy and heart failure.
• To investigate the role of p53 signaling in the progression of heart failure.

Main Methods:

• Integration of single-cardiomyocyte transcriptomics with cell morphology, epigenomics, and heart function data.
• Analysis of cardiomyocyte gene expression patterns in response to pressure overload.
• Utilizing cardiomyocyte-specific p53 deletion models.
• Validation in human single-cardiomyocyte samples.

Main Results:

• Early hypertrophy involves activation of mitochondrial translation/metabolism genes, linked to ERK1/2 and NRF1/2 pathways and cell size.
• Persistent overload leads to a bifurcation into adaptive and failing cardiomyocyte states.
• p53 signaling is specifically activated in late hypertrophy, driving mitochondrial inhibition, cell elongation, and heart failure gene activation.
• p53-independent mechanisms initiate hypertrophy, while p53-dependent pathways mediate failure progression.
• Pathogenic transcriptional signatures are conserved in human hearts.

Conclusions:

• Cardiomyocyte identity and phenotype are dictated by specific transcriptional programs.
• A sequential model of cardiac remodeling involves p53-independent hypertrophy followed by p53-dependent heart failure.
• These findings provide insights into the molecular basis of heart failure progression.