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  • 1
    Online Resource
    Online Resource
    DNA damage and repair in a model of rat vascular injury
    Portland Press Ltd. ; 2010
    In:  Clinical Science Vol. 118, No. 7 ( 2010-04-01), p. 473-485
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 118, No. 7 ( 2010-04-01), p. 473-485
    Abstract: Restenosis rates following vascular interventions still limit their long-term success. Oxidative stress plays a relevant role in this pathophysiological phenomenon, but less attention has been devoted to its effects on DNA damage and to the subsequent mechanisms of repair. In the present study, we analysed in a model of arteriotomy-induced stenosis in rat carotid arteries the time-dependent expression of DNA damage markers and of DNA repair genes, together with the assessment of proliferation and apoptosis indexes. The expression of the oxidative DNA damage marker 7,8-dihydro-8-oxo-2′-deoxyguanosine was increased at 3 and 7 days after arteriotomy, with immunostaining distributed in the injured vascular wall and perivascular tissue. Expression of the DNA damage marker phospho-H2A.X was less relevant, but increased from 4 h to 7 days after arteriotomy, with immunostaining prevalently present in the adventitia and, to a lesser extent, in medial smooth muscle cells at the injury site. RT (reverse transcription)–PCR indicated a decrease in eight out of 12 genes involved in the DNA repair machinery we selected from 4 h to 7 days after arteriotomy, with the exception of an increase in the Mutyh and Slk genes (P & lt;0.05). Western blot analysis revealed a decrease in p53 and catalase at 3 days after arteriotomy (P & lt;0.05). A maximal 7% of BrdU-positive cells in the endothelium and media occurred at 7 days after arteriotomy, whereas the apoptotic index peaked at 3 days after injury (P & lt;0.05). In conclusion, our results highlight a persistent DNA damage, presumably related to a temporary decrease in the expression of the DNA repair machinery and of the antioxidant enzyme catalase, playing a role in stenosis progression.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20090416
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2010
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  • 2
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    Online Resource
    Early cell changes and TGFβ pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis
    Portland Press Ltd. ; 2013
    In:  Clinical Science Vol. 124, No. 2 ( 2013-01-01), p. 97-108
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 124, No. 2 ( 2013-01-01), p. 97-108
    Abstract: Previous studies on BAV (bicuspid aortic valve)-related aortopathy, whose aetiology is still debated, have focused mainly on severe dilatations. In the present study, we aimed to detect earlier signs of aortopathy. Specimens were collected from the ‘concavity’ (lesser curvature) and the ‘convexity’ (greater curvature) of mildly dilated AAs (ascending aortas; diameter ≤4 cm) with stenotic TAV (tricuspid aortic valve) or BAV and from donor normal aortas. Specimens were submitted to morphometry, immunohistochemistry and differential gene-expression analysis, focusing on SMC (smooth muscle cell) phenotype, remodelling, MF (myofibroblast) differentiation and TGFβ (transforming growth factor β) pathway. Smoothelin and myocardin mRNAs decreased in all the samples from patients, with the exception of those from BAV convexity, where a change in orientation of smoothelin-positive SMCs and an increase of α-SMA (α-smooth muscle actin) mRNA occurred. Dilated aortas from BAV and TAV patients showed both shared and distinct alterations concerning the TGFβ pathway, including an increased TGFβ and TGFβR2 (TGFβ receptor 2) expression in both groups and a decreased TGFβR1 expression in BAV samples only. Despite a decrease of the mRNA coding for the ED-A (extra domain-A) isoform of FN (fibronectin) in the BAV convexity, the onset of the expression of the corresponding protein in the media was observed in dilated aortas, whereas the normal media from donors was negative for this isoform. This discrepancy could be related to modifications in the intima, normally expressing ED-A FN and showing an altered structure in mild aortic dilatations in comparison with donor aorta. Our results suggest that changes in SMC phenotype and, likely, MF differentiation, occur early in the aortopathy associated with valve stenosis. The defective expression of TGFβR1 in BAV might be a constitutive feature, while other changes we reported could be influenced by haemodynamics.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20120324
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2013
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  • 3
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    Online Resource
    Injury to rat carotid arteries causes time-dependent changes in gene expression in contralateral uninjured arteries
    Portland Press Ltd. ; 2009
    In:  Clinical Science Vol. 116, No. 2 ( 2009-01-01), p. 125-136
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 116, No. 2 ( 2009-01-01), p. 125-136
    Abstract: Vascular surgery aimed at stenosis removal induces local reactions often leading to restenosis. Although extensive analysis has been focused on pathways activated in injured arteries, little attention has been devoted to associated systemic vascular reactions. The aim of the present study was to analyse changes occurring in contralateral uninjured rat carotid arteries in the acute phase following unilateral injury. WKY (Wistar–Kyoto) rats were subjected to unilateral carotid arteriotomy. Contralateral uninjured carotid arteries were harvested from 4 h to 7 days after injury. Carotid arteries were also harvested from sham-operated rats and uninjured rats. Carotid morphology and morphometry were examined. Affymetrix microarrays were used for differential analysis of gene expression. A subset of data was validated by real-time RT–PCR (reverse transcription–PCR) and verified at the protein level by Western blotting. A total of 1011 genes were differentially regulated in contralateral uninjured carotid arteries from 4 h to 7 days after arteriotomy (P & lt;0.0001; fold change, ≥2) and were classified into 19 gene ontology functional categories. To a lesser extent, mRNA variations also occurred in carotid arteries of sham-operated rats. Among the changes, up-regulation of members of the RAS (renin–angiotensin system) was detected, with possible implications for vasocompensative mechanisms induced by arteriotomy. In particular, a selective increase in the 69 kDa isoform of the N-domain of ACE (angiotensin-converting enzyme), and not the classical somatic 195 kDa isoform, was observed in contralateral uninjured carotid arteries, suggesting that this 69 kDa isoenzyme could influence local AngII (angiotensin II) production. In conclusion, systemic reactions to injury occur in the vasculature, with potential clinical relevance, and suggest that caution is needed in the choice of controls during experimental design in vivo.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20080080
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2009
    Location Call Number Limitation Availability
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