Glycoxydation promotes vascular damage via MAPK-ERK/JNK pathways

J Cell Physiol. 2012 Nov;227(11):3639-47. doi: 10.1002/jcp.24070.

Abstract

Oxidation and glycation enhance foam cell formation via MAPK/JNK in euglycemic and diabetic subjects. Here, we investigated the effects of glycated and oxidized LDL (glc-oxLDL) on MAPK-ERK and JNK signaling pathways using human coronary smooth muscle cells. Glc-oxLDL induced a broad cascade of MAPK/JNK-dependent signaling transduction pathways and the AP-1 complex. In glc-oxLDL treated coronary arterioles, tumor necrosis factor (TNF) α increased JNK phosphorylation, whereas protein kinase inhibitor dimethylaminopurine (DMAP) prevented the TNF-induced increase in JNK phosphorylation. The role of MKK4 and JNK were then investigated in vivo, using apolipoprotein E knockout (ApoE(-/-)) mice. Peritoneal macrophages, isolated from spontaneously hyperlipidemic but euglycemic mice showed increases in both proteins and phosphorylated proteins. Compared to streptozotocin-treated diabetic C57BL6 and nondiabetic C57BL6 Wt mice, in streptozotocin-diabetic ApoE(-/-) mice, the increment of foam cell formation corresponded to an increment of phosphorylation of JNK1, JNK2, and MMK4. Thus, we provide a first line of evidence that MAPK-ERK/JNK pathways are involved in vascular damage induced by glycoxidation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E* / genetics
  • Apolipoproteins E* / metabolism
  • Cells, Cultured
  • Coronary Vessels / cytology
  • Coronary Vessels / metabolism
  • Diabetes Mellitus, Experimental
  • Foam Cells / cytology
  • Foam Cells / metabolism
  • Glycation End Products, Advanced
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Lipoproteins, LDL / pharmacology
  • MAP Kinase Signaling System* / drug effects
  • MAP Kinase Signaling System* / genetics
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase Kinases* / drug effects
  • Mitogen-Activated Protein Kinase Kinases* / genetics
  • Muscle, Smooth, Vascular / cytology
  • Oxidation-Reduction
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Apolipoproteins E
  • Glycation End Products, Advanced
  • Lipoproteins, LDL
  • Protein Kinase Inhibitors
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • glycated lipoproteins, LDL
  • oxidized low density lipoprotein
  • Mitogen-Activated Protein Kinase Kinases