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c-Myc antisense oligonucleotides preserve smooth muscle differentiation and reduce negative remodelling following rat carotid arteriotomy

Forte, A; Galderisi, U; De Feo, M; Gomez, Maria LU ; Esposito, S; Sante, P; Renzulli, A; Agozzino, L; Hellstrand, Per LU and Berrino, L, et al. (2005) In Journal of Vascular Research 42(3). p.214-225
Abstract
Objectives: The vascular biology of restenosis is complex and not fully understood, thus explaining the lack of effective therapy for its prevention in clinical settings. The role of c-Myc in arteriotomy-induced stenosis, smooth muscle cell (SMC) differentiation and apoptosis was investigated in rat carotids applying full phosphorothioate antisense ( AS) oligonucleotides (ODNs). Methods: Carotid arteries from WKY rats were submitted to arteriotomy and to local application of ODNs through pluronic gel. Apoptosis ( deoxynucleotidyl transferase-mediated dUTP nick end-labelling), SMC differentiation (SM22 immunofluorescence) and vessel morphology and morphometry ( image analysis) were determined 2, 5 and 30 days after injury, respectively.... (More)
Objectives: The vascular biology of restenosis is complex and not fully understood, thus explaining the lack of effective therapy for its prevention in clinical settings. The role of c-Myc in arteriotomy-induced stenosis, smooth muscle cell (SMC) differentiation and apoptosis was investigated in rat carotids applying full phosphorothioate antisense ( AS) oligonucleotides (ODNs). Methods: Carotid arteries from WKY rats were submitted to arteriotomy and to local application of ODNs through pluronic gel. Apoptosis ( deoxynucleotidyl transferase-mediated dUTP nick end-labelling), SMC differentiation (SM22 immunofluorescence) and vessel morphology and morphometry ( image analysis) were determined 2, 5 and 30 days after injury, respectively. Results: AS ODNs induced a 60% decrease of target c-Myc mRNA 4 h after surgery in comparison to control sense ( S) and scrambled ODN-treated carotids (p < 0.05). A significant 37 and 50% decrease in SM22 protein in the media of S ODN-treated and untreated carotids was detected when compared to uninjured contralateral arteries (p < 0.05). This reduction in SM22 expression was prevented in AS ODN-treated carotids. Stenosis was mainly due to adventitial constrictive remodelling. Lumen area in AS ODN-treated carotids was 35% greater than in control arteries 30 days after surgery (p < 0.05). TUNEL assay revealed increased apoptosis in AS ODN-treated carotids (p < 0.05). Conclusions: c-Myc AS ODNs reduce arteriotomy-induced negative remodelling. This is accompanied by maintained SMC differentiation and greater apoptosis. The combination of reduced c-Myc-induced proliferation and increased apoptosis may thus underlie the less severe remodelling upon treatment with c-Myc mRNA AS ODN. (Less)
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Contribution to journal
publication status
published
subject
keywords
antisense oligonucleotides, SM22, arteriotomy, c-Myc, stenosis, apoptosis, adventitia
in
Journal of Vascular Research
volume
42
issue
3
pages
214 - 225
publisher
Karger
external identifiers
  • wos:000229574400004
  • scopus:20644469260
ISSN
1423-0135
DOI
10.1159/000085379
language
English
LU publication?
yes
id
1a8a1b82-7531-47a7-962f-485545def431 (old id 238691)
date added to LUP
2007-08-07 12:59:46
date last changed
2017-01-01 07:00:01
@article{1a8a1b82-7531-47a7-962f-485545def431,
  abstract     = {Objectives: The vascular biology of restenosis is complex and not fully understood, thus explaining the lack of effective therapy for its prevention in clinical settings. The role of c-Myc in arteriotomy-induced stenosis, smooth muscle cell (SMC) differentiation and apoptosis was investigated in rat carotids applying full phosphorothioate antisense ( AS) oligonucleotides (ODNs). Methods: Carotid arteries from WKY rats were submitted to arteriotomy and to local application of ODNs through pluronic gel. Apoptosis ( deoxynucleotidyl transferase-mediated dUTP nick end-labelling), SMC differentiation (SM22 immunofluorescence) and vessel morphology and morphometry ( image analysis) were determined 2, 5 and 30 days after injury, respectively. Results: AS ODNs induced a 60% decrease of target c-Myc mRNA 4 h after surgery in comparison to control sense ( S) and scrambled ODN-treated carotids (p &lt; 0.05). A significant 37 and 50% decrease in SM22 protein in the media of S ODN-treated and untreated carotids was detected when compared to uninjured contralateral arteries (p &lt; 0.05). This reduction in SM22 expression was prevented in AS ODN-treated carotids. Stenosis was mainly due to adventitial constrictive remodelling. Lumen area in AS ODN-treated carotids was 35% greater than in control arteries 30 days after surgery (p &lt; 0.05). TUNEL assay revealed increased apoptosis in AS ODN-treated carotids (p &lt; 0.05). Conclusions: c-Myc AS ODNs reduce arteriotomy-induced negative remodelling. This is accompanied by maintained SMC differentiation and greater apoptosis. The combination of reduced c-Myc-induced proliferation and increased apoptosis may thus underlie the less severe remodelling upon treatment with c-Myc mRNA AS ODN.},
  author       = {Forte, A and Galderisi, U and De Feo, M and Gomez, Maria and Esposito, S and Sante, P and Renzulli, A and Agozzino, L and Hellstrand, Per and Berrino, L and Cipollaro, M and Cotrufo, M and Rossi, F and Cascino, A},
  issn         = {1423-0135},
  keyword      = {antisense oligonucleotides,SM22,arteriotomy,c-Myc,stenosis,apoptosis,adventitia},
  language     = {eng},
  number       = {3},
  pages        = {214--225},
  publisher    = {Karger},
  series       = {Journal of Vascular Research},
  title        = {c-Myc antisense oligonucleotides preserve smooth muscle differentiation and reduce negative remodelling following rat carotid arteriotomy},
  url          = {http://dx.doi.org/10.1159/000085379},
  volume       = {42},
  year         = {2005},
}