Estrogen is known to play an important role in protecting women’s hearts, but when estrogen levels decline after menopause, women are at increased risk of many diseases, including heart disease, obesity and diabetes.Recently, researchers from the University of Melbourne, Australia, published a paper in the Nature subjournal Nature Cardiovascular Research entitled: Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart- The research paper, entitled: Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart- derived extracellular vesicle proteome and induces obesity in female mice.
In this study, cardiomyocyte-specific ERα knockout (ERαHKO) mice were constructed and characterised to assess the role of ERα in the heart, and it was found that estrogen receptor alpha (ERα) in cardiomyocytes in the heart can regulate female obesity. Specifically, reduced ERα expression in cardiomyocytes resulted in moderate cardiac dysfunction and increased obesity rates in female mice, but not in males.
These multi-omics studies reveal a cardiac contractile and sex-specific cardiometabolic phenotype regulated by ERα, and provide new insights into extracellular vesicle (EV)-mediated inter-organ communication.
Estrogen receptor alpha (ERα) dysregulation is associated with increased risk of metabolic and cardiovascular disease, and paper correspondence author Professor Julie McMullen said the team had always wanted to understand the role of this estrogen receptor in the heart and see how it provides protection for the heart. When estrogen receptor alpha (ERα) was blocked, it was thought that changes and damage would be seen mainly to the heart. However, the result was to see an obese phenotype in the female mice, which was completely unexpected.
In addition to the most significant change, which led to obesity in female mice, the team also found that female mice with cardiomyocyte-specific ERα knockout (ERαHKO) showed cardiac dysfunction, mild glucose and insulin intolerance, and reduced ERα gene expression in skeletal muscle and white adipose tissue. Transcriptomic, proteomic, lipidomic and metabolomic analyses revealed contractile and/or metabolic dysregulation in cardiac, skeletal muscle and white adipose tissue.
The team also found that the heart-derived Extracellular Vesicles (EV) of ERαHKO female mice contained a unique proteome associated with lipid and metabolic regulation, which differed from the EV proteome of control and ERαHKO male mice.
In addition, extracellular vesicles (EV) released from cardiomyocytes in ERαHKO female mice have the ability to reprogram the skeletal muscle cell proteome in cell culture, resulting in functional effects on the glycolytic capacity and reserve of the cells. The result is that energy is not consumed but stored, which explains why reduced ERα levels lead to increased adiposity and obesity in female mice.
The findings and potential mechanisms of the cardiomyocyte-specific ERα knockout (ERαHKO) female mouse phenotype are summarised based on functional and multi-omics analyses.
This study provides a better understanding of the role of ERα in women who tend to become obese after receiving drugs or chemotherapy that can interact with or inhibit ERα, opening up new opportunities for finding therapeutic approaches to prevent obesity.
In addition, this study also shows that extracellular vesicles and the molecular cargo they carry are systemic signalling regulators that can reach and affect other organs and tissues in the body, including adipose tissue and skeletal muscle. This also provides a new case for the role of extracellular vesicle-mediated information exchange between cells, tissues and organs in health and disease.
This important work has implications for the prevention and treatment of cardiac and metabolic disease in postmenopausal women, as well as cardiotoxicity in premenopausal women receiving treatments that may inhibit or reduce cardiac ERα.
