Sex-Specific Response to A1BG Loss Results in Female Dilated Cardiomyopathy.

ABSTRACT

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.