C. Yang1,2, L. Belaygorod1, C. Feng3, C. F. Semenkovich3, M. Zayed1 1Washington University,Section Of Vascular Surgery,Department Of Surgery, Washington University School Of Medicine,St. Louis, MO, USA 2Huazhong University Of Science And Technology,Department Of Vascular Surgery,Union Hospital, Tongji Medical College,Wuhan, Hubei, China 3Washington University,Division Of Endocrinology, Metabolism, And Lipid Research, Department Of Medicine,,St. Louis, MO, USA
Introduction: Intracellular lipid metabolism is essential for endothelial cell activation and function. However, it is unknown to what extent this affects atheroprogression. We recently observed that choline ethanolamine phosphotransferase (CEPT1), a central enzyme in phospholipogenesis, is upregulated in peripheral arterial plaque of patients with clinical risk factors such as diabetes. In these patients, plaque phospholipid profiles were also reflective of increased CEPT1 activity. We hypothesize that CEPT1 may be an important EC regulator of plaque progression. To test this, we evaluated aortic atheroprogression in an adult apoe-/- mice following selective conditional endothelial knockdown of cept1.
Methods: Tamoxifen-induced VE-Cadherin driven cre expression and recombination of Loxp (Lp) flanked exon3 of the cept1 was used to induce selective gene knockdown in the endothelium of adult apoe-/- mice (cept1Lp/Lp apoe-/-). Six week old apoe-/- and cept1Lp/Lp apoe-/- mice were maintained on a western diet (42% fat content) for 12 weeks. Aortic atheroprogression was then evaluated and quantified following Oil red O staining.
Results:Whole mount aortic staining revealed that cept1Lp/Lp apoe-/- mice had markedly reduced aortic plaque volumes, particularly in the areas of high sheer stress such as the aortic arch (p < 0.05; Fig1A) and infrarenal aorta (p < 0.05; Fig1B). Histologic analysis of the aortic root intima also revealed significantly reduced Oil red O staining in cept1Lp/Lp apoe-/- mice (p < 0.05; Fig1C).
Conclusion:Conditional knockdown of cept1 in the endothelium of adult apoe-/- mice is atheroprotective. This novel observation demonstrates the critical role of CEPT1 in plaque progression, and invites further investigation regarding its potential therapeutic targeting to reduce atheroprogression.
