Abstract: AIM To identify whether vascular activity factors that can combine and inhibit the ability of APN are relate to vascular APN resistance in early phase hyperlipidemia.METHODS Twenty male Sprague Dawley rats were divided equally into control group and hyperlipidemia group randomly, receive regular diet or high-fat diet for 8 weeks, then triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein in circulation were determined. Plasma from regular diet and high-fat diet rats was applied co-immunoprecipitation with anti-APN antibody to precipitate plasma APN then followed mass spectrometric analysis to determine which vascular activity factors can combine with APN.Pre-incubated rAPN with vascular activity factors which discovered in former step and observed the AMPK activation effect of rAPN in HUVECs.RESULTS Compared with rats fed with regular diet rats fed with high-fat diet triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein and APN levels in circulation were obviously raised(P<0.05 or P<0.01)after 8 weeks.Discovered ApoA1,ApoC1,PON1 along with other fifteen vascular activity factors can combine APN and the ability of combination significantly increased in hyperlipidemia plasma (P<0.01).Among the eighteen vascular activity factors ApoA1 significantly increased in hyperlipidemia plasma (P<0.05),ApoA1 and ApoC1 can significantly inhibit the ability of rAPN to phosphorylate AMPK in HUVECs (P<0.01 or P<0.05).CONCLUSION Increased apolipoprotein that can combine and inhibit the activity of APN in hyperlipidemic plasma is likely responsible for vascular APN resistance in early phase hyperlipidemia.