The earliest lesion is the """"""""fatty streak,"""""""" consisting of monocyte-derived macrophages engorged with lipids. Fatty streaks can progress to more advanced stages of atherosclerotic lesions susceptible to plaque rupture and thrombosis. Many factors can influence lesion progression, such as cholesterol levels, hypertension, diabetes, smoking, and male gender. Current medical therapy is aimed at reducing these risk factors. Of particular interest is the treatment for women. It has long been thought that estrogens would reduce the risk by raising high density lipoproteins and improving endothelial function. For many years, clinicians have placed their post-menopausal patients on hormone replacement therapy (HRT). Unfortunately, a recent large clinical trial suggests HRT may not be as effective as we had once believed. Therefore understanding this disease process and developing new therapies specifically aimed at women is of great medical importance. Atherosclerosis is a complex and chronic inflammatory process. Macrophages play an important role in the development of atherosclerotic lesions and are thus an attractive target for drug therapy. The anti- diabetic drugs called glitazones activate peroxisome proliferator-activated receptor gamma (PPARg) exert both pro- and anti-atherogenic properties targeted at macrophages. Unexpectedly, intervention studies revealed that glitazones reduced atherosclerosis in male but not in female Ldlr-/- mice despite similar anti- inflammatory effects in both sexes. In a subsequent study using ovariectomized mice, rosiglitazone improved insulin and lipoprotein levels, but still failed to inhibit atherosclerosis. Additionally, glitazones reduced foam cell formation only in male macrophages. Functional studies showed that rosiglitazone failed to decrease cholesterol esterification or increase cholesterol efflux in female macrophages. Although women respond to the antidiabetic effects of glitazones, it is unclear whether they can exert anti-atherogenic effects in women. These observations suggest the male macrophage is a target of PPARg and the pathway responsible for the inhibition of foam cell formation is absent in female macrophages. One difference between male and female macrophages is the presence of the androgen receptor (AR). Preliminary results demonstrate that rosiglitazone fails to inhibit atherosclerosis in male Ldlr-/- mice reconstituted with either female or AR-/- cells. To identify the sexual dimorphism, I propose the following:
Specific Aim 1 : Determine that the anti- atherogenic effect of PPARg is inherent to male macrophages and dependent on AR expression.
Specific Aim 2 : Define the relationship between PPARg and AR.
Specific Aim 3 : Identify genes responsible for the sexual dimorphism.
Specific Aim 4 : Validate the results in human macrophages. Although the relationship between murine and human atherosclerosis is unclear, the results will provide a better understanding of PPARg's role in atherogenesis and may help in the development of drugs specifically targeted at women.
| Douglas, Robert M; Bowden, Karen; Pattison, Jennifer et al. (2013) Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice. J Appl Physiol (1985) 115:1694-704 |
| Saijo, Kaoru; Collier, Jana G; Li, Andrew C et al. (2011) An ADIOL-ER?-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145:584-95 |
| Tsimikas, Sotirios; Miyanohara, Atsushi; Hartvigsen, Karsten et al. (2011) Human oxidation-specific antibodies reduce foam cell formation and atherosclerosis progression. J Am Coll Cardiol 58:1715-27 |
| Bischoff, Eric D; Daige, Chris L; Petrowski, Mary et al. (2010) Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J Lipid Res 51:900-6 |
