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Published on: May 16, 2020
Sex-specific response to A1BG loss results in female dilated cardiomyopathy
James I Emerson1,2, Wei Shi1,2,3, Frank L Conlon4,5
1Departments of Biology and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Insights
Alpha-1-glycoprotein (A1BG) is crucial for maintaining female heart structure, preventing remodeling and early-stage dilated cardiomyopathy (DCM). Its absence causes sex-specific cardiac changes.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Sex-Specific Pathophysiology
Background:
- Cardiac diseases exhibit significant sex-specific differences in incidence and progression.
- The molecular underpinnings of these sex-specific cardiac pathologies are not fully understood.
- Alpha-1-glycoprotein (A1BG) is identified as a female-specific regulator of cardiac integrity, but its exact function requires further characterization.
Purpose of the Study:
- To elucidate the sex-specific role of A1BG in cardiac structure and function.
- To investigate the molecular pathways influenced by A1BG in the heart.
- To determine the consequences of A1BG loss on cardiac remodeling and disease predisposition.
Main Methods:
- Generation of conditional A1bg knockout and knockin mouse models.
- Comprehensive analysis including histology, electrocardiography, RNA sequencing (RNA-seq), transmission electron microscopy (TEM), western blotting, mass spectrometry, and immunohistochemistry.
- Assessment of structural, functional, and molecular phenotypes in a sex-specific manner.
Main Results:
- Loss of A1BG in cardiomyocytes induced persistent structural remodeling exclusively in female hearts, characterized by ventricular dilation and wall thinning, indicative of early-stage dilated cardiomyopathy (DCM).
- Transcriptomic analysis revealed A1BG's regulation of critical metabolic pathways in females, including glucose-6-phosphate and acetyl-CoA metabolism.
- TEM imaging demonstrated sex-specific disruption of intercalated disc architecture in female cardiomyocytes lacking A1BG.
Conclusions:
- A1BG is essential for maintaining ventricular structural integrity in female hearts, but not male hearts.
- The absence of A1BG leads to chronic pathological remodeling in females, potentially increasing susceptibility to DCM.
- These findings highlight A1BG as a key sex-specific factor in cardiac health and disease.
Background:
Cardiac disease often manifests with sex-specific differences in frequency, pathology, and progression. However, the molecular mechanisms underlying these differences remain incompletely understood. The glycoprotein A1BG has emerged as a female-specific regulator of cardiac structure and integrity, yet its precise role in the female heart is not well characterized.
Methods:
To investigate the sex-specific role of A1BG in the heart, we generated both a conditional A1bg knockout allele and an A1bg Rosa26 knockin allele. We employed histological analysis, electrocardiography, RNA sequencing (RNA-seq), transmission electron microscopy (TEM), western blotting, mass spectrometry, and immunohistochemistry to assess structural, functional, and molecular phenotypes.
Results:
Loss of A1BG in cardiomyocytes leads to persistent structural remodeling in female, but not male, hearts. Despite preserved systolic function in female A1bgCM/CM mice left ventricular dilation and wall thinning are evident and sustained over time, consistent with early-stage dilated cardiomyopathy (DCM). Transcriptomic analyses reveal that A1BG regulates key metabolic pathways in females, including glucose-6-phosphate and acetyl-CoA metabolism. TEM imaging highlights sex-specific disruption of intercalated disc architecture in female cardiomyocytes. These findings suggest that the absence of A1BG initiates chronic pathological remodeling in female hearts, potentially predisposing them to DCM under stress or aging.
Conclusion:
A1BG is essential for maintaining ventricular structural integrity in female, but not male, hearts, leading to a chronic remodeling consistent with early-stage DCM.
