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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 orcid ; 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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author
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organization
publishing date
type
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
2016-04-01 16:15:08
date last changed
2025-04-04 14:13:48
@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}},
  keywords     = {{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}},
  doi          = {{10.1159/000085379}},
  volume       = {{42}},
  year         = {{2005}},
}