Abstract 1519: Urotensin-II Receptor Knockout Increases Plasma Lipids and Atherosclerosis in ApoE Knockout Mice
Objective: We have demonstrated that the UII system is up-regulated in human coronary, carotid, and aortic atherosclerosis. Furthermore, UII plays a role in both smooth muscle cell proliferation and foam cell formation. Therefore, we sought to determine the effect of UT gene deletion in a mouse model of atherosclerosis.
Methods: UT knockout (KO) mice were developed by homologous recombination using the neomycin phosphotransferase gene cassette. These mice were then crossed with ApoE KO mice to develop UT/ ApoE double knockout (DKO) mice. At 6 weeks of age wild-type (WT), UT KO, ApoE KO, and DKO mice were placed on a high fat western type diet for 12 weeks. We evaluated the degree of atherosclerosis via an en face aortic presentation, and the lesion area was quantified and compared to total aortic area.
Results: ApoE KO mice showed apparent aortic atherosclerosis and hepatic steatosis. Negligible atherosclerosis was observed in either WT or UT KO mice. However, DKO mice exhibited significantly increased atherosclerosis compared to ApoE KO mice (P<0.05). This was associated with a significant increase in total plasma cholesterol (P<0.001), serum triglycerides (P<0.001), and decrease in hepatic steatosis (P<0.001). In addition, DKO mice exhibited significant heart, kidney, and spleen hypertrophy (P<0.01). While both UT KO mice and DKO mice exhibited significant reductions in liver mass compared to WT mice and ApoE KO mice, respectively (P<0.05). In addition, DKO mice exhibited significantly increased glomerular collagen deposition(p<0.001).
Conclusions: Here we show that UT gene deletion in an ApoE KO genetic background exacerbates hyperlipidemia, which is associated with increased aortic lesion formation, as well as, heart, kidney, and spleen hypertrophy. The profound hyperlipidemia in DKO mice may be due to altered liver metabolism of lipids as evidenced by the significantly decreased hepatic steatosis in these mice.