Tail vein injection of mmLDL upregulates mouse mesenteric artery ETB receptors via activation of the ERK1/2 pathway

Vascul Pharmacol. 2017 Sep:96-98:33-39. doi: 10.1016/j.vph.2017.08.002. Epub 2017 Aug 7.

Abstract

Minimally modified low density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. This study investigated the effect of mmLDL on mouse mesenteric artery endothelin type B (ETB) receptors and its molecular mechanism. Mice were injected with normal saline (NS group), mmLDL in the tail vein (mmLDL group), or with both mmLDL and an intraperitoneal injection of the ERK1/2 pathway-specific inhibitor U0126 (mmLDL+U0126 group). The dose-response curve of mesenteric artery contraction induced by sarafotoxin 6c (S6c), the ETB receptor agonist, was measured using a sensitive myograph system. ELISAs, RT-PCR and Western blot were used to determine the serum concentrations of mouse oxidized low density lipoprotein (oxLDL), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) as well as the expression of ETB receptors, ICAM-1, VCAM-1 and phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2). The S6c-induced contraction dose-response curve was significantly enhanced by mmLDL treatment and showed a significantly higher Emax value than in the NS group (P<0.001), and the ETB receptor mRNA and protein expression in the vascular wall was significantly higher than in the NS group. The serum concentration and expression of ICAM-1 and VCAM-1 were also increased by mmLDL treatment, but intraperitoneal injection of U0126 inhibited these changes as well as the increase in p-ERK1/2 protein in the vessel wall caused by mmLDL. ICAM-1 and VCAM-1 serum concentrations were positively correlated with the S6c-induced maximum contraction of blood vessels. Increased in vivo levels of mmLDL increased the serum concentrations and expression of ICAM-1 and VCAM-1 by activating the ERK1/2 pathway, resulting in the expression of ETB receptors and the enhancement of contractile function in vascular smooth muscle. Understanding the effect of mmLDL on ETB receptors and its mechanism can provide ideas for cardiovascular disease prevention and treatment.

Keywords: 5-hydroxytryptamine (PubChem CID: 21,701,104); Acetylcholine (PubChem CID: 187); Dimethylsulfoxide (PubChem CID: 21,584,481); ERK1/2; ET(B) receptor; ICAM-1; Mesenteric artery; Sarafotoxin 6c (PubChem CID: 16,132,429); Tail vein injection; U0126 (PubChem CID: 3,006,531); VCAM-1; mmLDL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Female
  • In Vitro Techniques
  • Injections, Intravenous
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lipoproteins, LDL / administration & dosage*
  • Male
  • Mesenteric Arteries / drug effects*
  • Mesenteric Arteries / enzymology
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Nitriles / pharmacology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, Endothelin B / drug effects*
  • Receptor, Endothelin B / metabolism
  • Signal Transduction / drug effects*
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vasoconstriction / drug effects*
  • Vasoconstrictor Agents / pharmacology
  • Viper Venoms / pharmacology

Substances

  • Butadienes
  • EDNRB protein, mouse
  • Icam1 protein, mouse
  • Lipoproteins, LDL
  • Nitriles
  • Protein Kinase Inhibitors
  • Receptor, Endothelin B
  • U 0126
  • Vascular Cell Adhesion Molecule-1
  • Vasoconstrictor Agents
  • Viper Venoms
  • oxidized low density lipoprotein
  • sarafotoxins s6
  • Intercellular Adhesion Molecule-1
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3