Chondroitin sulfate N-acetylgalactosaminyltransferase-2 deletion alleviates lipoprotein retention in early atherosclerosis and attenuates aortic smooth muscle cell migration

Biochem Biophys Res Commun. 2019 Jan 29;509(1):89-95. doi: 10.1016/j.bbrc.2018.12.068. Epub 2018 Dec 20.

Abstract

Glycosaminoglycans (GAGs) play an integral role in low-density lipoprotein (LDL) retention in the vascular intimal layer and have emerged as attractive therapeutic targets for atherosclerosis. GAG biosynthesis involves the cooperation of numerous enzymes. Chondroitin sulfate N-acetylgalactosaminyltransferase-2 (ChGn-2) is a vital Golgi transferase that participates in enzymatic elongation of GAGs. Here, we investigated the effects of ChGn-2 gene deletion on the development of atherosclerosis. Partial carotid artery ligation was performed on ChGn-2-/-/LDLr-/- and ChGn-2+/+/LDLr-/- mice to induce diffuse intimal thickening (DIT). Aortic smooth muscle cells (ASMCs) were isolated to investigate cellular LDL binding and migration. Histological analysis of human coronary artery sections revealed that ChGn-2 was expressed in early and advanced atherosclerotic lesions. Deletion of the ChGn-2 gene significantly reduced LDL retention in the DIT mouse model. Furthermore, LDL binding, visualized using rhodamine-labeled LDLs, was dramatically reduced. Interestingly, a functional assay of ASMCs prepared from ChGn-2-/- mice displayed abrogation of platelet-derived growth factor (PDGF)-mediated migration via reduced PDGF receptor phosphorylation. Taken together, these findings indicate that ChGn-2 is functionally involved in the progression of atherosclerosis both in its early and advanced stages. Therefore, ChGn-2 may serve as a plausible target to treat atherosclerotic-related diseases in the future.

Keywords: Atherosclerosis; ChGn-2; Glycosaminoglycan; LDL retention; Platelet-derived growth factor; Response to retention theory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Aorta / cytology
  • Aorta / metabolism
  • Aorta / pathology*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Cell Movement
  • Cells, Cultured
  • Gene Deletion
  • Humans
  • Lipoproteins / analysis
  • Lipoproteins / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • N-Acetylgalactosaminyltransferases / genetics
  • N-Acetylgalactosaminyltransferases / metabolism*
  • Phosphorylation
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Young Adult

Substances

  • Lipoproteins
  • N-Acetylgalactosaminyltransferases
  • chondroitin sulfate N-acetylgalactosaminyltransferase-2
  • Receptors, Platelet-Derived Growth Factor