title: 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).
abstract: 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.
  
  
  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.
authors.affiliation: Department of Clinical Chemistry, Institute of Biomedical Technology and BioMediTech, and Department of Pathology, Fimlab Laboratories, University of Tampere and Tampere University Hospital, Tampere, Finland; and Division of Vascular Surgery, Department of Surgery and Heart Center, and Department of Clinical Physiology, Tampere University Hospital, University of Tampere, Tampere, Finland.
authors.forename: Niku
authors.initials: N
authors.lastname: Oksala
authors.forename: Jenita
authors.initials: J
authors.lastname: Pärssinen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Seppälä
authors.forename: Emma
authors.initials: E
authors.lastname: Raitoharju
authors.forename: Ivana
authors.initials: I
authors.lastname: Kholova
authors.forename: Kholova
authors.initials: K
authors.lastname: Ivana
authors.forename: Jussi
authors.initials: J
authors.lastname: Hernesniemi
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.forename: Mari
authors.initials: M
authors.lastname: Levula
authors.forename: Kari-Matti
authors.initials: KM
authors.lastname: Mäkelä
authors.forename: Thanos
authors.initials: T
authors.lastname: Sioris
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.forename: Vesa
authors.initials: V
authors.lastname: Hytönen
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D000075386:Netrin Receptors; D000075388:Netrin-1; D020411:Oligonucleotide Array Sequence Analysis; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000199:Actins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C532445:UNC5B protein, human; D000075388:Netrin-1
keywords: atherosclerosis; gene expression; immunohistochemistry; macrophages; myocytes; smooth muscle; whole genome association analysis