Effects Of Blood Pressure And Salt On Arterial Lipid Deposition In The Apoe-Depleted Shr

Objective: Hypertension and oxidative stress are both risk factors for atherosclerosis. Although apoprotein E (ApoE)-knockout mice have been widely used as a model for atherosclerosis, chronic effects of high blood pressure (BP) were not fully elucidated because of lack of hypertensive models in mice. In this study, we therefore constructed ApoE-knockout SHR (ApoE-KO SHR) to address this issue. As SHR is a genetic model for hypertension, ApoE-KO SHR would be a good model to evaluate effects of hypertension on atherosclerosis. Here, we examined effects of blood pressure and salt-loading on the ApoE-KO SHR. Design and method: ApoE-KO SHR was made using the genome editing technology with CRISPR/CAS9. We successfully obtained ApoE-KO SHR with 13 bps deletion causing a frame-shift. ApoE-KO SHR was then backcrossed with WKY for 3 generations to make an ApoE-KO model with lower BP (ApoE-KO WKY). Rats were fed high-fat diet for 8 weeks from 8 weeks of age with or without 1% salt water. Rats were then sacrificed and lipid deposition in mesenteric arteries were evaluated on microscope. Results: In ApoE-KO rats, serum total cholesterol and triglyceride were dramatically increased. Under salt-loading condition, oxidative stress estimated with urinary isoprostane was significantly increased. BP in ApoE-KO SHR and ApoE-KO WKY were comparable with that in SHR and WKY, respectively. Under the salt-loading condition, lipid deposition in mesenteric arteries was significantly greater in ApoE-KO SHR than in ApoE-KO WKY. Conclusions: These results suggested that high blood pressure and/or salt aggravated arterial lipid deposition in mesenteric arteries probably through endothelial dysfunction in the salt-loaded ApoE-KO SHR.