Abstract
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 in vivo, 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 ETA receptor mRNA expression was detected using real-time polymerase chain reactions, and the protein levels of the ETA receptor, class III PI3K, Beclin-1, LC3 II/I, p62, NF-κB, and p-NF-κB were observed using Western blot analysis. mmLDL significantly strengthened ET-1-induced contraction (the Emax value increased from 184.87 ± 7.46% in the NS group to 319.91 ± 20.31% in the mmLDL group (P < 0.001), and the pEC50 value increased from 8.05 ± 0.05 to 9.11 ± 0.09 (P < 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 ETA receptor and increased the protein level of p-NF-κB. However, these effects were significantly inhibited by 3-MA. mmLDL activates autophagy via the Class III PI3K/Beclin-1 pathway and upregulates the ETA receptor via the downstream NF-κB pathway. Understanding the effect of mmLDL on the ETA receptor and the underlying mechanisms may provide a new idea for the prevention and treatment of cardiovascular diseases.
Highlights
Autophagy is an evolutionally conserved metabolic process; as an important survival mechanism, it degrades and turns over organelles and cytoplasmic contents [1]. e autophagy process consists of the formation of bilayer-membrane autophagosomes, the phagocytosis of cytoplasmic substances, and the fusion of autophagosomes with lysosomes for degradation. e formation of autophagosomes depends on the assembly of Beclin-1- and Class III PI3K-containing phospholipid kinase signaling complexes. ese complexes mediate the nucleation of the autophagosomal precursor and activate two ubiquitin-like binding pathways (Atg5Atg12 and microtubule-associated protein light-chain 3phospholipid conjugates) to promote separation and membrane expansion [2, 3]
This study indicated that caudal vein injection of Minimally modified low-density lipoprotein (mmLDL) could upregulate the endothelin type A (ETA) receptor level in mouse arteriomesenteric smooth cells to strengthen ETA receptor-mediated vasoconstriction
This study discovered that the Class III PI3K/Beclin-1 autophagy pathway participated in the regulation of the arteriomesenteric ETA receptor level in mice in vivo for the first time
Summary
Autophagy is an evolutionally conserved metabolic process; as an important survival mechanism, it degrades and turns over organelles and cytoplasmic contents [1]. e autophagy process consists of the formation of bilayer-membrane autophagosomes, the phagocytosis of cytoplasmic substances, and the fusion of autophagosomes with lysosomes for degradation. e formation of autophagosomes depends on the assembly of Beclin-1- and Class III PI3K-containing phospholipid kinase signaling complexes. ese complexes mediate the nucleation of the autophagosomal precursor and activate two ubiquitin-like binding pathways (Atg5Atg and microtubule-associated protein light-chain 3phospholipid conjugates) to promote separation and membrane expansion [2, 3]. Ese complexes mediate the nucleation of the autophagosomal precursor and activate two ubiquitin-like binding pathways (Atg5Atg and microtubule-associated protein light-chain 3phospholipid conjugates) to promote separation and membrane expansion [2, 3]. In myocytes with the specific knockout of ETA receptors, aging-induced myocardial hypertrophy and contractile dysfunction are improved, during which autophagy exerts an important role [6]. MmLDL induces the adhesion of monocytes to endothelial cells to generate colony-stimulating factors, monocyte chemotactic protein-1, and tissue factors, which causes damage to endothelial cells and promotes oxLDL generation; mmLDL can activate multiple apoptotic signaling pathways in human coronary artery cells [9]. For the first time, we explored the effect of mmLDL on arteriomesenteric ETA receptors in vivo and the role of autophagy in this process. For the first time, we explored the effect of mmLDL on arteriomesenteric ETA receptors in vivo and the role of autophagy in this process. e results of this study may deepen the understanding of the vascular biological mechanisms of mmLDL
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Advances in pharmacological and pharmaceutical sciences
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
