MmLDL Activates The PI3K/Akt Pathway To Upregulate Mouse Mesenteric Artery ET_B Receptors And ?₁ Receptors

Purpose and background lipoprotein?LDL?is a spherical granulosaprotein,the core part of LDL is cholesteryl ester,which is surrounded by phospholipids,free cholesterol,and apolipoprotein B-100?apoliprotein B100,apoB-100?.LDL can be oxidized by oxygen radicals and its metabolic intermediates in vivo.Oxidation products are related to the degree of oxidation and oxidation sites.When the lipid fraction of LDL is oxidized,the product is minimally oxidized low-density lipoprotein?mmLDL?.If both the lipid portion and the apolipoprotein portion of LDL are oxidized at the same time,the product is oxidized low density lipoprotein?ox-LDL?,both mmLDL and ox-LDL are important risk factor for cardiovascular disease.The previous study of our group found that mmLDL can impair endothelium-dependent relaxation of mesenteric arteries in vivo,It can increase the expression of endothelin type B receptor in isolated rat coronary artery and basilar artery.mmLDL can upregulated the expression of ET_B receptor and?₁ receptor and its mediated contraction in mesenteric artery of mice by activates ERK1/2pathway.this study was aim to investigate the relationship between mmLDL upregulat ET_B receptor and?₁ receptor in mesenteric artery of mice with PI3K/Akt pathway.Methods Tail vein injection mmLDL and intraperitoneal injection phosphatidylinositol 3-kinase?PI3K?specific inhibitor LY294002,Remove mouse mesenteric artery endothelium,The vascular tension of mice mesenteric artery induced by Sarafotoxin 6c?S6c?and Phenylephrine?PE?were measured by DMT.The serum concentration of oxidized low density lipoprotein?ox-LDL?were detected using ELISA kit.The protein expression levels of PI3 K,p-PI3 K,p-Akt,ET_B receptor and?₁ receptor were detected using Western blot.The mRNA levels of ET_B receptor and?₁ receptor were detected using real-time polymerase chain reaction?RT-PCR?.Results The contraction of mesenteric arteries induced by tail vein injection of mmLDL was significantly increased,while PI3 K inhibitor LY294002 significantly inhibited this effect.The results showed that the mean E_maxof S6 c and PE-mediated vasoconstriction in mmLDL group was significantly higher than that in normal saline group?NS??P<0.001?,while LY294002 decreased the E_maxof vasoconstriction mediated by S6 c and PE from?119.86±5.25?%and?263.16±27.13?%of the mmLDL group to?43.47±8.58?%?P<0.001?and?175.70±17.88?%?P<0.001?.In addition,compared with the NS group,mmLDL increase the expression of ET_B,?₁ receptor mRNA and protein in mouse mesenteric artery?P<0.001?,and intraperitoneal injection PI3 K inhibitor LY294002 significantly inhibited this effect.Compared to mmLDL group,ET_B receptor and?₁ receptor protein levels and mRNA levels were obviously reduced?P<0.001?.Compared with NS group,mmLDL significantly enhance the expression of p-PI3 K and p-Akt in mouse mesenteric artery?P<0.01?,While LY294002 significantly inhibited this effect?P<0.01?.Conclusions mmLDL increases the expression and vasoconstri-ction of ET_B receptor and?₁ receptor in mouse mesenteric artery by active PI3K/Akt signaling pathway.