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1.
FASEB J ; 11(12): 1021-31, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9337155

ABSTRACT

It has been hypothesized that mutational events may be involved in the atherogenetic process and that at least a portion of atherosclerotic plaques may develop according to an initiation-promotion process of arterial smooth muscle cells, akin to benign tumors. We conducted a study to evaluate the occurrence of oxidative DNA damage and formation of DNA adducts in human atherosclerotic lesions and to assess the relationships of these promutagenic alterations with exposure to atherogenic risk factors. Pure DNA was extracted from the tunica media (composed mainly of smooth muscle cells) of abdominal aorta fragments taken at surgery from 85 patients suffering from severe atherosclerotic lesions. DNA adducts were detected by synchronous fluorescence spectrophotometry and 32P postlabeling after enrichment of adducts with either butanol or nuclease P1. 8-Hydroxy-2'-deoxyguanosine (8-OH-dG), a typical indicator of oxidative DNA damage, was measured by HPLC/electrochemical detection. A complete questionnaire reporting general, clinical, and laboratory characteristics was available for each patient. All 84 samples tested by 32P postlabeling were positive by displaying the presence of diagonal radioactive zones and up to 9 individual DNA adducts. Of 52 samples tested, 32 (61.5%) yielded typical positive signals at synchronous fluorescence spectrophotometry. All but one of 39 samples tested had very high levels of 8-OH-dG, thus showing a remarkable oxidative DNA damage. Statistically significant correlations were found between the levels of molecular biomarkers and atherogenic risk factors including age, number of currently smoked cigarettes, ratio of total-to-high density lipoprotein blood cholesterol, blood triglycerides, and blood pressure. The DNA alterations detected in our study may be only one component of the genetic basis of atherogenesis. Moreover, no causal role in the atherogenetic process can be inferred from our results. However, DNA alterations, including oxidative damage and adduction of reactive molecules of either endogenous or exogenous source, were systematically present in the smooth muscle cells of human atherosclerotic lesions and their intensity was significantly correlated with the occurrence of atherogenic risk factors in the patients studied.


Subject(s)
Aorta, Abdominal/pathology , Arteriosclerosis/epidemiology , DNA Adducts/analysis , DNA Damage/genetics , 8-Hydroxy-2'-Deoxyguanosine , Aorta, Abdominal/chemistry , Arteriosclerosis/genetics , Arteriosclerosis/pathology , Arteriosclerosis/surgery , Chromatography, High Pressure Liquid , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/analysis , Humans , Molecular Epidemiology , Muscle, Smooth, Vascular/chemistry , Muscle, Smooth, Vascular/pathology , Spectrometry, Fluorescence
2.
Chem Biol Interact ; 102(1): 55-62, 1996 Sep 27.
Article in English | MEDLINE | ID: mdl-8827062

ABSTRACT

In the framework of a project investigating the possible involvement of cancer biomarkers in human atherogenesis, we evaluated the occurrence of K-ras mutations in the DNA extracted from smooth muscle cells of abdominal aorta atherosclerotic lesions. The molecular analysis of the DNA from 32 surgical specimens, using PCR-based denaturing gradient gel electrophoresis (DGGE), did not reveal any variant in K-ras codons 12 and 13, which are the most frequently involved codons among the ras genes mutated in various types of human tumors. Analysis of the DNA extracted from four cell lines carrying known K-ras mutational alleles showed typically positive DGGE patterns. Thus, on the whole, the conclusions of this study and of previous studies using the same biological material are consistent with the occurrence of DNA adducts in human atherosclerotic lesions but in the absence of p53 involvement or of K-ras mutations in codons 12 and 13. The search for candidate genes which may possibly be involved in the atherogenetic process warrants further studies.


Subject(s)
Arteriosclerosis/genetics , Codon/genetics , Genes, ras/genetics , Aged , Aged, 80 and over , Animals , Aorta, Abdominal/chemistry , Base Sequence , Cell Line , DNA/analysis , DNA/isolation & purification , Female , Humans , Male , Mice , Middle Aged , Molecular Sequence Data , Mutation , Nucleic Acid Heteroduplexes/analysis , Polymerase Chain Reaction
3.
Cancer Epidemiol Biomarkers Prev ; 4(2): 105-10, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7742716

ABSTRACT

Since somatic mutations are suspected to contribute to the pathogenesis not only of cancer but also of atherosclerotic plaques, we measured DNA adducts in the smooth muscle layer of atherosclerotic lesions in abdominal aorta specimens taken at surgery from seven patients. DNA adducts were evaluated in three laboratories by means of different molecular dosimetry methods, including: (a) HPLC/fluorescence, which specifically identifies the DNA adducts of the anti-benzo(a)pyrene (BPDE) isomer; (b) two- and three-dimensional synchronous fluorescence spectrophotometries, which detect DNA adducts of BPDE and other reactive metabolites of polycyclic aromatic hydrocarbons; and (c) 32P postlabeling, which reveals the presence of a variety of types of DNA adducts. The HPLC/fluorescence method provided for the first time evidence for the presence of BPDE-DNA specific adducts in three of six specimens tested. Synchronous fluorescence spectrophotometry displayed broad areas of fluorescence in all seven specimens, thereby suggesting the occurrence not only of BDPE-DNA but also of other DNA adducts with similar fluorescence characteristics. All specimens were also positive at 32P postlabeling, which revealed multiple spots detectable following enrichment either with nuclease P1 or butanol, indicative of the presence of different aromatic DNA adducts. Thus, the data obtained by applying typical cancer biomarkers provide further support to the hypothesis that there may be similarities between the carcinogenic and the atherogenic processes, and in particular that genetic alterations caused by DNA-binding agents in the artery wall may be detected in atherosclerotic lesions.


Subject(s)
Aortic Diseases/metabolism , Arteriosclerosis/metabolism , Biomarkers, Tumor/analysis , DNA Adducts/analysis , Aged , Aged, 80 and over , Aorta, Abdominal/chemistry , Aortic Diseases/genetics , Arteriosclerosis/genetics , Benzo(a)pyrene/analysis , Butanols/analysis , Chromatography, High Pressure Liquid , Female , Fluorescence , Humans , Male , Middle Aged , Muscle, Smooth, Vascular/chemistry , Phosphorus Radioisotopes , Polycyclic Compounds/analysis , Single-Strand Specific DNA and RNA Endonucleases/analysis , Spectrometry, Fluorescence
4.
Cancer Epidemiol Biomarkers Prev ; 4(2): 111-5, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7742717

ABSTRACT

In order to assess similarities between the atherogenic and the carcinogenic processes, we investigated whether the p53 tumor suppressor gene, the most commonly altered gene in human cancer, may be also involved in human atherosclerotic lesions. The medium layers of abdominal aorta fragments taken at surgery from 32 patients were subjected to immunohistochemical analysis, using either monoclonal (Pab 1801) or polyclonal (CM-1) antibodies, and to molecular analysis by the PCR-based denaturing gradient gel electrophoresis approach. The results obtained indicated that p53 mutations are not involved in the pathogenesis of atherosclerotic lesions, and that no accumulation of the wild-type protein occurs in smooth muscle cells of these lesions. A polymorphism characterized by an AT to GC transition at codon 213 (CGA --> CGG) causing no aminoacid substitution (Arg --> Arg) was detected in the 10.5% of the examined patients. Our negative findings do not support the hypothesis that the atherosclerotic plaques may be pathogenetically akin to benign tumors yet they are not in contrast with this theory, since in most cases p53 is involved in advanced stages of the carcinogenesis process.


Subject(s)
Aortic Diseases/genetics , Aortic Diseases/metabolism , Arteriosclerosis/genetics , Arteriosclerosis/metabolism , Biomarkers, Tumor/analysis , Genes, p53/genetics , Aged , Aged, 80 and over , Antibodies, Monoclonal , Aorta, Abdominal/chemistry , Arginine , Base Sequence , Biomarkers, Tumor/genetics , Codon/genetics , Electrophoresis, Polyacrylamide Gel , Exons/genetics , Female , Guanine , Humans , Immunohistochemistry , Male , Middle Aged , Molecular Sequence Data , Muscle, Smooth, Vascular/chemistry , Mutation/genetics , Polymerase Chain Reaction , Polymorphism, Genetic/genetics
8.
Chir Ital ; 35(4): 554-8, 1983 Aug.
Article in Italian | MEDLINE | ID: mdl-6680862

ABSTRACT

A new instrument, specially devised and constructed for varicose saphenous vein branches excision through small skin incisions non requiring suture, is described. The instrument's utilization in the surgical treatment of varices of the lower limbs is explained. The significant shortening of the whole surgical procedure and the optimal cosmetic appearance of the operated limbs, are the most outstanding advantages of the presented technique compared with the commonly employed ones.


Subject(s)
Saphenous Vein/surgery , Surgical Instruments , Varicose Veins/surgery , Humans
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