Studies investigating sex hormone influences on heart disease
Young men are twice as likely as young women to die from cardiovascular disease. This could be due to genetic, lifestyle and/or hormonal influences. Hormones are readily amenable to therapeutic intervention and a lot of research has focussed on elucidating the influence of female hormones, estrogens, on cardiovascular disease. However, in our laboratory we are instead focussing on the effects of male hormones, androgens, on atherosclerosis. The hypothesis is that life long exposure to androgens may predispose young men to earlier atherosclerotic plaque development. If androgens underlie, even partly, the gender difference in cardiovascular disease, then careful consideration must be given to the increasing clinical application of androgens in the treatment of hormone deficiency states and for hormonal male contraception.
Our ongoing research has identified a novel androgen-sensitive step in the earliest stage of atherosclerotic plaque development, namely the increased expression of the key adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 mediates the binding, and subsequent migration, of monocytes into the vessel wall. The androgen stimulated increase in VCAM-1 expression is dependent on the activation of the key inflammatory regulator, nuclear factor-kappaB. These findings may provide clues to the earlier onset of atherosclerosis in men. Further studies are now underway to more fully explore the molecular pathways triggered by androgens in all key vascular cells associated with atherosclerosis including monocytes, endothelial cells and smooth muscle cells.
We are also using genetic mouse models of cardiovascular disease to study why men are predisposed to earlier onset cardiovascular disease. One of our major studies is based on the Barker hypothesis that prenatal exposure to nutritional and hormonal effects can impact on late-life degenerative diseases, including cardiovascular disease. In this study we are determining the effect of pre-natal- and peri-natal androgen exposure on late-life cardiovascular disease.