Association of neuroimmune guidance cue netrin-1 and its chemorepulsive receptor UNC5B with atherosclerotic plaque expression signatures and stability in human(s): Tampere Vascular Study (TVS)

Circ Cardiovasc Genet. 2013 Dec;6(6):579-87. doi: 10.1161/CIRCGENETICS.113.000141. Epub 2013 Oct 11.


Background: Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its receptors and their association with plaque stability in human(s) is lacking.

Methods and results: The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (-2.9-fold; P<0.0001) and UNC5B upregulated (2.2-fold; P<0.0001) in atherosclerotic plaques (n=68), whereas there were no differences in other NTN1 receptors compared with histologically normal controls (n=28). Increased UNC5B expression is associated with histologically more stable plaques (P=0.011). NTN1 expression correlated positively with SMC markers and signatures and negatively with inflammatory markers and M1 and especially M2 signatures in the atherosclerotic plaques. UNC5B clustering correlated positively with inflammatory and MΦ markers. NTN1 protein colocalized with CD68-positive cells of monocytic origin and muscle-actin-specific-antibody (HHF3)-positive cells indicative of SMCs in the plaques and only with SMCs in the control samples. NTN1 protein was highly expressed in the intimal layer of the control vessels.

Conclusions: Present findings provide support for the hypothesis that dysregulation of expression of NTN1 in SMCs and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques.

Keywords: atherosclerosis; gene expression; immunohistochemistry; macrophages; myocytes; smooth muscle; whole genome association analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Aged
  • Aged, 80 and over
  • Cluster Analysis
  • Down-Regulation
  • Female
  • Gene Expression Profiling*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Macrophages / metabolism
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Monocytes / metabolism
  • Myocytes, Smooth Muscle / metabolism
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / metabolism
  • Netrin Receptors
  • Netrin-1
  • Oligonucleotide Array Sequence Analysis
  • Plaque, Atherosclerotic / genetics*
  • Plaque, Atherosclerotic / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation


  • Actins
  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • UNC5B protein, human
  • Netrin-1