Cardiac effects of ovarian hormones and gender in a mouse model of obesity

Men are at higher risk to develop obesity, cardiovascular disease and hypertension than women. However, this tendency is inversed in the postmenopausal population when women lose their advantage while ovarian hormone levels decrease. This raises the question as to why and how this occurs. Many studies suggested that estrogen is cardioprotective, however the underlying mechanisms are still unknown. Additionally, hormone replacement therapies failed to prove the beneficial effect of estrogen on the cardiovascular system. Hence the need to characterize and better understand the mechanisms underlying the effects of estrogen in the cardiovascular system. Thus, the aim of this thesis project was to describe gender- and ovarian hormone-specific effects of obesity in the heart. To this end we analyzed the effect of HFD, gender and ovariectomy on cardiac function and structure and investigated the mechanisms involved in a mouse model.
Male and female mice were fed for 22 weeks with a regular chow diet and a high-fat diet (HFD) containing 45% calories derived from saturated fat and 17% from sucrose aiming to mimic the diet used in western countries, which contains a lot of saturated fat and carbohydrates. The following gender-specific changes were demonstrated after HFD feeding. At the systemic level, male showed a stronger increase of plasma insulin than female mice, suggestive of higher insulin sensitivity in the female mice. Cardiac function analysis revealed that the peak filling and emptying rates were decreased by the HFD in male mice only, suggesting that their ventricular relaxation is impaired. As for the female mice, they exhibited decreased E/A ratios as well as a moderate wall thickness increase, suggestive of mild diastolic dysfunction and cardiac remodeling, respectively. Ejection fractions were preserved in these female mice.
To evaluate the role of female hormones in changing cardiac structure and function, we ablated the ovaries (OVX) 4 weeks before starting the diet. At the systemic level, we demonstrated that ovarian hormones are involved in increasing plasma insulin and maintaining glucose tolerance in response to HFD, since the OVX-female mice were not able to increase plasma insulin levels and had greater glucose intolerance than the sham-female mice after HFD. When investigating cardiac function, we revealed that the sham-female but not the OVX-female mice were able to reduce the end-diastolic pressure in response to HFD. This difference unveiled that OVX-female had higher end-diastolic pressures than sham-female mice after HFD following cardiac stress induced by the beta-adrenergic agonist dobutamine. This suggests that estrogen is implicated in the adaptation to the increased cardiac work induced by dobutamine. Finally, we demonstrated that OVX-female had higher cardiac PDK4 mRNA than sham-female mice when fed with regular chow, suggesting that ovarian hormones are important for preserving normal glucose oxidation. In conclusion, these data suggest that estrogen plays a role in insulin and glucose homeostasis as well as in the adaptation of the heart to HFD-induced obesity.