Abstract 209: An XX Sex Chromosome Complement Promotes the Development of Obesity, Hypercholesterolemia and Atherosclerosis in Male and Female Ldlr -/- Mice Fed a Western Diet

Abstract

Background: Underlying mechanisms contributing to sexual dimorphism of cardiovascular diseases are not well understood. Sex hormones are primary contributors to sexual dimorphism of cardiovascular diseases. By comparison, little is known regarding the contribution of genes on sex chromosomes (XX and XY) to sexual dimorphism of cardiovascular diseases, even though the X chromosome contains around 5% of the human genome. In this study, we hypothesized that genes on sex chromosomes influence the development of obesity, hypercholesterolemia and atherosclerosis. Methods and Results: Transgenic male mice with deletion of Sry from the Y-chromosome expressing Sry on autosomes (8-12 weeks of age) were bred to female Ldlr -/- mice to generate female and male mice with an XX or an XY sex chromosome complement (FXX, FXY, MXX, MXY). Mice were fed a Western diet (Teklad TD88137) for 3 months. XX mice exhibited increased body weight compared to mice with an XY sex chromosome complement, regardless of gonadal sex (FXX, 41.2 ± 2.4; FXY, 31.7 ± 2.5 g; P<0.05; MXX, 51.5 ± 1.2; MXY, 41.7 ± 1.8 g; P<0.05). Moreover, XX mice had increased serum cholesterol concentrations, regardless of gonadal sex (FXX, 2501 ± 192; FXY, 890 ± 141 mg/dl; P<0.05; MXX, 3814 ± 344; MXY, 1297 ± 385 mg/dl; P<0.05). Elevations in serum lipids were manifest as increased VLDL and LDL-cholesterol. The extent of atherosclerosis in aortic arch was significantly increased in XX compared to XY mice (XXF, 37 ± 2.1; XYF, 20 ± 3.2; XXM, 38 ± 3.6; XYM, 24 ± 3.6 % lesion surface area; P<0.05). In the aortic sinus, atherosclerotic lesion surface area was significantly increased in XX mice, regardless of gonadal sex (FXX, 60.4 x 10 4 ± 3.6 x 10 4 ; FXY, 32.4 x 10 4 ± 3.8 x 10 4 μm 2 ; P<0.05; MXX, 67.1 x 10 4 ± 9.6 x 10 4 ; MXY, 36.2 x 10 4 ± 3.7 x 10 4 μm 2 ; P<0.05). Conclusion: Results demonstrate that an XX sex chromosome complement promotes diet-induced obesity, hypercholesterolemia and atherosclerosis regardless of gonadal sex. Future studies will identify the role of genes on the X or Y chromosome as mechanisms for these effects.