4-hydroxy-2-nonenal and Hyperplasia

Topics: Aldehydes; Animals; Arteries; Arteriovenous Shunt, Surgical; Cell Proliferation; Down-Regulation; Gene Expression; Glutathione Transferase; Hyperplasia; MAP Kinase Signaling System; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Phenotype; Phosphorylation; Renal Insufficiency, Chronic; RNA, Messenger; Tunica Intima; Veins

Saphenous veins used as arterial grafts are exposed to arterial levels of oxygen partial pressure (pO2), which are much greater than what they experience in their native environment. The object of this study is to determine the impact of exposing human saphenous veins to arterial pO2. Saphenous veins and left internal mammary arteries from consenting patients undergoing coronary artery bypass grafting were cultured ex vivo for 2 weeks in the presence of arterial or venous pO2 using an established organ culture model. Saphenous veins cultured with arterial pO2 developed intimal hyperplasia as evidenced by 2.8-fold greater intimal area and 5.8-fold increase in cell proliferation compared to those freshly isolated. Saphenous veins cultured at venous pO2 or internal mammary arteries cultured at arterial pO2 did not develop intimal hyperplasia. Intimal hyperplasia was accompanied by two markers of elevated reactive oxygen species (ROS): increased dihydroethidium associated fluorescence (4-fold, p<0.05) and increased levels of the lipid peroxidation product, 4-hydroxynonenal (10-fold, p<0.05). A functional role of the increased ROS saphenous veins exposed to arterial pO2 is suggested by the observation that chronic exposure to tiron, a ROS scavenger, during the two-week culture period, blocked intimal hyperplasia. Electron paramagnetic resonance based oximetry revealed that the pO2 in the wall of the vessel tracked that of the atmosphere with a ~30 mmHg offset, thus the cells in the vessel wall were directly exposed to variations in pO2. Monolayer cultures of smooth muscle cells isolated from saphenous veins exhibited increased proliferation when exposed to arterial pO2 relative to those cultured at venous pO2. This increased proliferation was blocked by tiron. Taken together, these data suggest that exposure of human SV to arterial pO2 stimulates IH via a ROS-dependent pathway.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Aldehydes; Arteries; Free Radical Scavengers; Humans; Hyperplasia; Lipid Peroxidation; Oxygen; Reactive Oxygen Species; Saphenous Vein; Tunica Intima

Ex vivo culture of arteries and veins is an established tool for investigating mechanically induced remodeling. Porcine saphenous veins (PSV) cultured ex vivo with a venous mechanical environment, serum-supplemented cell-culture medium and standard cell-culture conditions (5% CO₂ and 95% balance air ~140 mmHg pO₂) develop intimal hyperplasia (IH), increased cellular proliferation, decreased compliance and exhibit inward eutrophic remodeling thereby suggesting that nonmechanical factors stimulate some changes observed ex vivo. Herein we explore the contribution of exposure to greater than venous pO₂ and serum to these changes in cultured veins. Removing serum from culture medium did not inhibit development of IH, but did reduce cellular proliferation and inward eutrophic remodeling. In contrast, veins perfused using reduced pO₂ (75 mmHg) showed reduced IH. Among the statically cultured vessels, veins cultured at arterial pO₂ (95 mmHg) and above showed IH as well as increase in proliferation and vessel weight compared to fresh veins; veins cultured at venous pO₂ did not. Taken together, these data suggest that exposure of SV to arterial pO₂ stimulates IH and cellular proliferation independent of changes in the mechanical environment, which might provide insight into the etiology of IH in SV used as arterial grafts.

Topics: Aldehydes; Animals; Arteries; Biomass; Biomechanical Phenomena; Carbon Dioxide; Cell Death; Cell Proliferation; Collagen; Hydrogen; Hyperplasia; In Situ Nick-End Labeling; Indoles; Mitotic Index; Oxygen; Partial Pressure; Perfusion; Pressure; Saphenous Vein; Serum; Sus scrofa; Tissue Culture Techniques; Tunica Intima

To clarify the role of oxidative stress during breast carcinogenesis by studying the expression of 8-hydroxydeoxyguanosine (8-OHdG) (a marker of oxidative DNA damage) and 4-hydroxy-2-nonenal (HNE) (a marker of lipid peroxidation) during the different phases of breast carcinogenesis.. The study material consisted of a total of 219 patients: 31 with usual ductal hyperplasia (UDH), 25 with atypical ductal hyperplasia (ADH), 30 with ductal carcinoma in situ (DCIS) and 133 with invasive carcinoma. The expression of 8-OHdG and HNE were evaluated immunohistochemically. Both 8-OHdG (77.4%) and HNE (45.8%) expression was already seen in UDH lesions. Interestingly, the trend of these two immunostainings during breast carcinogenesis was diverse. 8-OHdG expression diminished significantly in invasive breast carcinomas compared to non-invasive lesions (P < 0.005 when set against non-invasive cohorts). Also within the same lesions, 8-OHdG expression was the most intensive in benign cells. Conversely, HNE immunostaining was strongest in invasive breast carcinomas (UDH versus invasive cohort, P = 0.015).. 4-hydroxy-2-nonenal as a marker of lipid peroxidation increases during breast carcinogenesis, reflecting the role of oxidative stress in the pathogenesis of breast cancer. However, 8-OHdG shows diminished levels in carcinomas, possibly resulting from the induction of DNA repair in these invasive lesions.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Aldehydes; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Cell Transformation, Neoplastic; Deoxyguanosine; DNA Repair Enzymes; Female; Humans; Hyperplasia; Lipid Peroxidation; Middle Aged; Oxidative Stress; Retrospective Studies

The susceptibility of rat liver tissue to oxidative stress during its neoplastic transformation was analyzed by both qualitative and quantitative measurements of the carbonyl products of lipid peroxidation. Diethylnitrosamine was used as initiating agent of hepatocarcinogenesis and lipid peroxidation levels were monitored in the homogenates from normal liver, hyperplastic nodules and tumour, incubated in the presence or in the absence of ascorbate or adenosine diphosphate-iron complex. While the basal levels of lipid peroxidation in the three experimental conditions were found to be quite similar, in the presence of the pro-oxidant stimulus a remarkable reduction in aldehyde production was shown not only by the hepatoma tissue but also by the preneoplastic nodules.

Topics: Aldehydes; Animals; Arachidonic Acid; Arachidonic Acids; Cell Transformation, Neoplastic; Chromatography, High Pressure Liquid; Diethylnitrosamine; Fatty Acids; Hyperplasia; Lipid Peroxides; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Malondialdehyde; Oxidation-Reduction; Phosphatidylethanolamines; Rats; Rats, Inbred Strains