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A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure
Published on: April 30, 2020
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Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure
Pablo Cordero1,2, Victoria N Parikh1, Elizabeth T Chin1,2
1Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA.
Nature Communications
|June 26, 2019
Summary
Researchers mapped gene networks in human hearts to understand heart failure. They identified PPP1R3A as a key regulator, showing its role in disease and potential as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Genetics
- Systems Biology
Background:
- Heart failure is a major cause of death, with incomplete understanding of its genetic basis.
- Genetic interactions contributing to heart failure pathogenesis require further elucidation.
Purpose of the Study:
- To construct cardiac gene regulatory networks in healthy and failing human hearts.
- To identify key genetic regulators and cardiac expression quantitative trait loci (eQTLs) associated with heart failure.
- To investigate the role of PPP1R3A in heart failure progression.
Main Methods:
- Harvesting human hearts and obtaining genome-wide genotyping and gene expression data.
- Building and comparing cardiac regulatory gene networks between failing and non-failing hearts.
- Performing RNA sequencing after PPP1R3A knockdown and validating findings in mouse models.
Main Results:
- Constructed gene networks revealed significant changes in regulator connectivity between healthy and failing hearts.
- PPP1R3A was identified as a central regulator whose network role shifts in heart failure.
- PPP1R3A knockdown affected metabolic pathways and cardiomyocyte size; its absence protected mice from heart failure.
Conclusions:
- A global gene interaction map of the human heart failure transition was created.
- Novel cardiac eQTLs were identified, enhancing our understanding of heart failure genetics.
- PPP1R3A is a critical regulator in heart failure, highlighting the potential of disease-specific network analysis for therapeutic discovery.
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