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Sex-Specific Response to A1BG Loss Results in Female Dilated Cardiomyopathy
James I Emerson1, Wei Shi1, Frank L Conlon1
1University of North Carolina at Chapel Hill.
Insights
Glycoprotein A1BG is crucial for female heart health, preventing dilated cardiomyopathy. Its absence causes cardiac dysfunction specifically in females, highlighting sex-specific roles in cardiovascular health.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Sex-Based Differences in Medicine
Background:
- Cardiac disease exhibits sex-specific differences in frequency and pathology, yet underlying mechanisms remain unclear.
- The glycoprotein A1BG is essential for female cardiac function but not male cardiac function.
- The specific role of A1BG in the female heart is understudied.
Purpose of the Study:
- To investigate the sex-differential function of A1BG in cardiac structure and function.
- To elucidate the molecular mechanisms by which A1BG influences cardiac health in a sex-specific manner.
Main Methods:
- Generation of novel conditional A1bg allele and A1bg Rosa26 knockin mouse models.
- Comprehensive assessment using histology, electrocardiography, RNA-seq, electron microscopy, western blot, mass spectrometry, and immunohistochemistry.
- Analysis of cardiac structure, function, and molecular pathways.
Main Results:
- Absence of A1BG leads to significant cardiac dysfunction in female mice, but not male mice.
- A1BG is critical for metabolic processes and intercalated disc integrity in female cardiomyocytes.
- Sex-specific A1BG cardiac interactomes contribute to structural and functional alterations, including dilated cardiomyopathy in females.
Conclusions:
- Loss of A1BG in cardiomyocytes results in dilated cardiomyopathy exclusively in females.
- A1BG plays a critical, sex-specific role in maintaining female cardiac health.
Background:
Cardiac disease often manifests differently in terms of frequency and pathology between men and women. However, the mechanisms underlying these differences are not fully understood. The glycoprotein A1BG is necessary for proper cardiac function in females but not males. Despite this, the role of A1BG in the female heart remains poorly studied.
Methods:
To determine the sex differential function of A1BG, we generated a novel conditional A1bg allele and a novel conditional A1bg Rosa26 knockin allele. Histology, electrocardiography, transcriptional profiling (RNA-seq), transmission electron microscopy, western blot analyses, mass spectrometry, and immunohistochemistry were used to assess cardiac structure and function.
Results:
The study reveals that the absence of A1BG results in significant cardiac dysfunction in female but not male mice. Gene expression underscores that A1BG plays a critical role in metabolic processes and the integrity of intercalated discs in female cardiomyocytes. This dysfunction may be related to sex-specific A1BG cardiac interactomes and manifests as structural and functional alterations in the left ventricle indicative of dilated cardiomyopathy, thus suggesting a sex-specific requirement for A1BG in cardiac health.
Conclusion:
The loss of A1BG in cardiomyocytes leads to dilated cardiomyopathy in females, not males.
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