MmLDL Activates The ERK1/2 Pathway In Vivo To Upregulatemouse Mesenteric Artery ET_B Receptors

Objectives minimally modified low density lipoprotein(mmLDL) is a risk factor for the cardiovascular disease. This study was aimed to explore the effect of mmLDL treated by intravenous tail injections on the expression of mesenteric artery endothelin type B(ETB) receptor and its underlying molecular mechanism.Methods Wire myograph system was used to examine vascular tension of mesenteric arteries caused by ETB receptor agonist Sarafotoxin 6c(S6c). The serum concentration of oxidized low density lipoprotein(ox-LDL), ICAM-1, and VCAM-1 were detected using enzyme linked immune sorbent assay. The expressions of the ETB receptor, ICAM-1,VCAM-1, and p-ERK1/2 were detected using real-time polymerase chain reactions and western blot analysis.Results Compared with the NS group, the mmLDL group exhibited a significantly enhanced S6c’s concentration-contractile response curve and a noticeably increased Emax value(P <0.001).Also, ETB receptor mRNA and protein expression were significantly increased in the mmLDL group when compared with NS group. When compared with the NS group, LDL group did not substantially affect the ETB receptor-mediated contractile response curves, showing that LDL was not relevant to the enhanced ETB receptor-mediated vasoconstriction induced by mmLDL. Intraperitoneal injection of U0126, a specific antagonist of ERK1/2, significantly inhibited the enhanced S6c’s concentration-contractile response curve induced by mmLDL, as showed by a significantly decreased Emax value(P < 0.001). U0126 significantly inhibited the increased ETB receptor expression induced by mmLDL, showing that ETB receptor mRNA and protein levels were significantly lower than that of mmLDL group. The serum concentrations of ICAM-1 and VCAM-1 in the mmLDL group was significantly higher than that of the NS group. Moreover, there is a significant increase in the mRNA and protein expression levels of ICAM-1 and VCAM-1 in mmLDL group compared with NS group. Intraperitoneal injection of U0126 markedly inhibited the increases in the serum levels and vessel wall expression of ICAM-1 and VCAM-1 in the mmLDL group. There is a positive correlation between both serum levels of ICAM-1 and VCAM-1 and the S6c-induced maximum shrinkage percentage. U0126 inhibited the mmLDL-induced increase in the p-ERK1/2 protein level in the vessel wall.Conclusions mmLDL induces the increased expression of ETB receptor and the enhanced ETB receptor-mediated vasoconstriction, and its mechanism involves the activation of the ERK1/2 pathway. mmLDL increased the expression levels of ICAM-1 and VCAM-1 in vivo by activating the ERK1/2 pathway. There is a positive correlation between both serum levels of ICAM-1 and VCAM-1 and the ETB receptor expression, respectively.