The Class III PI3K/Beclin-1 Autophagic Pathway Participates in the mmLDL-Induced Upregulation of ET Receptor in Mouse Mesenteric Arteries.

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. The current study explored the effect of mmLDL on the endothelin type A (ETA) receptor in mouse mesenteric arteries , as well as the role of autophagy in this process. mmLDL was injected via the caudal vein, and the Class III PI3K autophagic pathway inhibitor 3-methyladenine (3-MA) was injected intraperitoneally. The animals were divided into physiological saline (NS), mmLDL, and mmLDL + 3-MA groups. The dose-effect curve of endothelin-1- (ET-1-) induced mesenteric artery contraction was measured using myography, while ET receptor mRNA expression was detected using real-time polymerase chain reactions, and the protein levels of the ET receptor, class III PI3K, Beclin-1, LC3 II/I, p62, NF-B, and p-NF-B were observed using Western blot analysis. mmLDL significantly strengthened ET-1-induced contraction (the value increased from 184.87 ± 7.46% in the NS group to 319.91 ± 20.31% in the mmLDL group ( < 0.001), and the pEC value increased from 8.05 ± 0.05 to 9.11 ± 0.09 ( < 0.01). In addition to upregulating the protein levels of Class III PI3K, Beclin-1, and LC3 II/I and downregulating that of p62, mmLDL significantly increased the mRNA expression and protein level of the ET receptor and increased the protein level of p-NF-B. However, these effects were significantly inhibited by 3-MA. mmLDL activates autophagy via the Class III PI3K/Beclin-1 pathway and upregulates the ET receptor via the downstream NF-B pathway. Understanding the effect of mmLDL on the ET receptor and the underlying mechanisms may provide a new idea for the prevention and treatment of cardiovascular diseases.