KCa3.1 channels mediate the increase of cell migration and proliferation by advanced glycation endproducts in cultured rat vascular smooth muscle cells

Lab Invest. 2013 Feb;93(2):159-67. doi: 10.1038/labinvest.2012.163. Epub 2012 Nov 19.

Abstract

The mechanisms underlying the involvement of advanced glycation endproducts (AGEs) in diabetic atherosclerosis are not fully understood. The present study was designed to investigate whether intermediate-conductance Ca(2+)-activated K(+) channels (K(Ca)3.1 channels) are involved in migration and proliferation induced by AGEs in cultured rat vascular smooth muscle cells (VSMCs) using approaches of whole-cell patch voltage-clamp, cell proliferation and migration assay, and western blot analysis. It was found that the current density and protein level of K(Ca)3.1 channels were enhanced in cells incubated with AGE-BSA (bovine serum albumin), and the effects were reversed by co-incubation of AGE-BSA with anti-RAGE (anti-receptors of AGEs) antibody. The ERK1/2 inhibitors PD98059 and U0126, the P38-MAPK inhibitors SB203580 and SB202190, or the PI3K inhibitors LY294002 and wortmannin countered the K(Ca)3.1 channel expression by AGE-BSA. In addition, AGE-BAS increased cell migration and proliferation, and the effects were fully reversed with anti-RAGE antibody, the K(Ca)3.1 channel blocker TRAM-34, or K(Ca)3.1 small interfering RNA. These results demonstrate for the first time that AGEs-induced increase of migration and proliferation is related to the upregulation of K(Ca)3.1 channels in rat VMSCs, and the intracellular signals ERK1/2, P38-MAPK and PI3K are involved in the regulation of K(Ca)3.1 channel expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Androstadienes
  • Animals
  • Blotting, Western
  • Butadienes
  • Cell Movement / physiology*
  • Cell Proliferation*
  • Cells, Cultured
  • Chromones
  • Flavonoids
  • Glycation End Products, Advanced / metabolism*
  • Imidazoles
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Morpholines
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / physiology*
  • Nitriles
  • Patch-Clamp Techniques
  • Pyridines
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Rats
  • Serum Albumin, Bovine
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Wortmannin

Substances

  • Androstadienes
  • Butadienes
  • Chromones
  • Flavonoids
  • Glycation End Products, Advanced
  • Imidazoles
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • Kcnn4 protein, rat
  • Morpholines
  • Nitriles
  • Pyridines
  • RNA, Small Interfering
  • U 0126
  • advanced glycation end products-bovine serum albumin
  • Serum Albumin, Bovine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • SB 203580
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Wortmannin