Why sex is relevant: New insight into the female heart
IEMR - Institute for Experimental Medical Research
Excellent cardiac research from bench to bedside
The Carlson group?at IEMR explores how men and women are different – at a molecular level!
Heart disease affects millions worldwide and has historically been described as a “man’s disease”. However, the gap in prevalence between men and women that suffers from heart disease is closing. Notably, women live longer and are at greater risk of heart disease in the second half of their life. Can biological differences explain these observations? As has been noted, “men are from Mars and women are from Venus”, but for heart disease, biological differences at a molecular level might be even more significant.
Why we need to think more about sex
Historically, an underwhelming volume of medical research has involved women, even though we know that male and female hearts respond differently to common diseases such as myocardial infarctions. Even in basic research, most experiments are carried out with male rodents. Among the possible consequences of this, is that women experience more adverse effects from medications, and that heart disease probably is underdiagnosed in women. Insight into female-specific disease mechanisms is crucial to discover therapeutic approaches tailored for women.
What we do
Cells in our bodies are packed with proteins that interact in networks. These networks, or signalling pathways, cause a domino effect inside the cells that affect the structure and function of the cells. The research in our group has focused on one signalling molecule that might be especially important in the female heart, called syndecan-4, which acts as a link between the exterior and interior of the cell. To better understand the molecular differences in the male and female heart, we have compared sex-dependent effects in rodents lacking this protein specifically. This is potentially important as syndecan-4 is known to associate with the incidence of heart attacks in females, but less so in males, suggesting the function of this protein varies between the sexes.
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Exploring the role of syndecan-4 in the female heart
Women and men have different risk factors for the development of heart disease. Metabolic syndromes, such as diabetes, are a common risk factor for heart disease, more so in women than men. At baseline, women are more sensitive to insulin, meaning a lower concentration of insulin is needed to exert the same effect as in males.
Sex hormones have been suggested to play an important role in insulin sensitivity.?Our results suggest that syndecan-4 may also be involved (St?le?et al., 2022): We have recently shown that rodents missing syndecan-4 have increased serum insulin levels. Insulin is able to activate a signalling pathway called “Akt”. The Akt signalling pathway is known to promote growth of tough fibrous tissue that makes it more difficult for the heart to beat and increases the size of the heart cells causing the heart to become bigger than it should. However, an elevation in Akt signalling is protective for the heart in females due to the female hormone estrogen, whereas the opposite is true for the male heart. Interestingly, we have found that female rodents missing syndecan-4 have an increase in the Akt signalling pathway, but males do not. Various other proteins in the Akt network, involved in insulin-Akt signallings, such as GSK-3β and GLUT4, are also altered in the female rodents lacking syndecan-4 (St?le?et al., 2022). We are currently investigating how these molecular changes affect hearts lacking syndecan-4 anatomically and functionally. Additionally, we are investigating how the differences we observe between the sexes play a role in the sick heart.
Through sex-inclusive research we can better understand how proteins such as syndecan-4 exert their role in a sex-dependent manner, contributing to the functioning of the healthy heart and its role in the development of disease.