Involvement Of ERK1/2 Pathway In MmLDL Upregulation Of ET_A Receptors In Mouse Mesenteric Arteries

Background:The production of minimally modified low density lipoprotein(mmLDL)is earlier than that of oxidized low density lipoprotein,which can represent the early form of oxidized low density lipoprotein.mmLDL is an important pathogenic factor in vascular diseases,but its mechanism is not completely clear.Extracellular signal-regulated kinase 1/2(ERK1/2)signaling pathway can regulate the proliferation and migration of vascular smooth muscle cells,participate in inflammation,stress and immunity,and play an important role in a variety of cardiovascular diseases.Endothelin type A(ETA)receptors,located on the nuclear membrane of vascular smooth muscle cells,are involved in vascular inflammation,remodeling and other pathological processes,and are closely related to the course of atherosclerosis.Purpose:To investigate whether mmLDL up-regulates ETA receptors in mouse mesenteric artery through ERK1/2 signaling pathway,providing new target for diagnosis,prevention and treatment of cardiovascular diseases.Methods:Mice were randomly divided into normal saline(NS),mmLDL,mmLDL+U0126,mmLDL+DMSO and LDL groups,and the volume-effect curves of contraction induced by the ETA agonist endothelin-1(ET-1)in mice mesenteric arteries were observed by microvascular tonometry.The protein expression levels of ERK,p-ERK and ETA receptor were detected by Western Blot,ETA receptor mRNA by RT-PCR and ETA receptor protein expression on mesenteric arteries by immunofluorescence assay.Results:mmLDL caused a significantly enhanced ET-1 contractile volume effect curve,as evidenced by an increase in Emax value from(179.63±3.93)%in the saline(NS)group to(291.44±12.67)%(P<0.01),a significant increase in the mRNA and protein expression levels of the ETA receptor,and a significant increase in the protein expression level of p-ERK.After intraperitoneal injection of ERK1/2 inhibitor U0126,the vasoconstrictor response was significantly reduced compared to the mmLDL group,as evidenced by a decrease in Emax values to(202.28±5.88)%(P<0.01),a significant decrease in mRNA and protein expression levels of ETA receptors,and a significant decrease in protein expression levels of p-ERK.Conclusion:mmLDL can upregulate ETA receptors in mouse mesenteric arteries by activating the ERK1/2 signalling pathway.