Oxidative stress is involved in the development of experimental abdominal aortic aneurysm: A study of the transcription profile with complementary DNA microarray

Yajima, Nobuyuki; Masuda, Masahisa; Miyazaki, Masaru; Nakajima, Nobuyuki; Chien, Shu; Shyy, John Y.‐J.

doi:10.1067/mva.2002.124366

Cited by 85 publications

(67 citation statements)

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“…12) In addition to activation of proteolysis and inflammation, apoptosis of smooth muscle cells 13) and oxidative stress 14,15) have been suggested by several clinicopathological studies, and these factors together with many others seem to be intricately interwoven to produce aneurysms. Another difficulty is that suitable animal models are not available for the study of aortic aneurysms.…”

Section: Discussionmentioning

confidence: 99%

Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms: Microarray Analysis of Surgically Resected Specimens

et al. 2005

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SUMMARYChanges in the expression levels of several genes have been described in aortic aneurysm specimens, however, the spectrum of diverse molecular alterations remains to be elucidated. We attempted to identify key molecules that modulate the pathogenesis of aortic aneurysm, using a complimentary DNA microarray carrying approximately 13,000 human genes.Segments of thoracic aortic aneurysms (TAA) and adjacent normal thoracic aortic tissues without aneurysmal changes (NTA) were obtained from 20 patients undergoing graft surgery. RNA obtained from five pairs of TAA and NTA samples was compared to determine aneurysm-specific alterations using microarray. Further, the expression levels of several genes of interest were verified in the remaining specimens by real-time reverse transcription-polymerase chain reaction (RT-PCR).In microarray assays, several types of the matrix metalloproteinases were upregulated as reported previously. Also, 220 genes suggested to be involved in protein degradation, inflammation, apoptosis, stress response, intracellular signaling, and other processes were significantly upregulated. Many of these genes have not been previously implicated in cardiovascular disease. The real time RT-PCR independently confirmed that the expression levels of MMP-2, MMP-9, ADAMTS-1, and caspase 4 were consistently increased in TAA.The results indicate that many genes are involved in a complicated manner in the pathogenesis of TAA. Investigation of these genes will help clarify the pathogenesis of this disease, and may lead to the discovery of novel therapeutic targets. (Int Heart J 2005; 46: 265-277)

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Section: Discussionmentioning

confidence: 99%

Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms: Microarray Analysis of Surgically Resected Specimens

et al. 2005

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“…Multiple studies in which tissue availability was not a limiting factor have consistently shown a correlation between differential gene expression identified through microarray analysis and realtime PCR. [15][16][17][18][19][20][21][22][23][24][25] Total RNA for real-time PCR analysis was extracted from liver tissue (ϳ5 mg) of subjects with NASH (n ϭ 6) and from 2 groups of control subjects without NASH (cirrhosis secondary to PBC, n ϭ 6), and body mass index, gender-and age-matched subjects with normal liver histology and biochemical profiles (healthy controls, n ϭ 6) by TRIZOL method (Life Technologies). One microgram of total RNA was treated with DNase (Life Technologies) and then reverse transcribed using the TaqMan Reverse Transcription Reagents (PE Biosystems, Foster City, CA) according to the manufacturer's instruction.…”

Section: Methodsmentioning

confidence: 99%

Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis

et al. 2003

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Although the molecular basis for the pathophysiology of nonalcoholic steatohepatitis (NASH) is poorly understood, insulin resistance and mitochondrial dysfunction are physiologic hallmarks of this condition. We sought evidence of a transcriptional or pretranscriptional basis for insulin resistance and mitochondrial dysfunction through measurement of hepatic gene expression (messenger RNA [mRNA]) using high-density synthetic oligonucleotide microarray analysis (Hu6800 GeneChip, Affymetrix, CA). Global hepatic gene expression was determined in snap-frozen liver biopsy specimens from 4 groups: (1) patients with cirrhotic-stage NASH (n ‫؍‬ 6), (2) patients with cirrhosis caused by hepatitis C virus (HCV) (n ‫؍‬ 6), (3) patients with cirrhosis secondary to primary biliary cirrhosis (PBC) (n ‫؍‬ 6), and (4) healthy controls (n ‫؍‬ 6). Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control groups. Sixteen genes were uniquely differentially expressed (4 overexpressed and 12 underexpressed) in patients with cirrhotic-stage NASH. Genes that were significantly underexpressed included genes important for maintaining mitochondrial function (copper/zinc superoxide dismutase, aldehyde oxidase, and catalase). Glucose 6-phospatase, alcohol dehydrogenase, elongation factor-TU, methylglutaryl coenzyme A (CoA), acyl CoA synthetase, oxoacyl CoA thiolase, and ubiquitin also were underexpressed in NASH. Genes that were overexpressed in NASH included complement component C3 and hepatocyte-derived fibrinogen-related protein, potentially contributing to impaired insulin sensitivity. In conclusion, these studies provide evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function (attenuated capacity for the dismutation of reactive oxygen species) and diminished insulin sensitivity (increased acute phase reactants) in patients with histologically progressive NASH. Further studies are required to determine the mechanism and the physiologic significance of these findings. (HEPATOLOGY 2003;38:244-251.)

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“…A number of studies have demonstrated that proinflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, can enhance inducible nitric oxide synthase (iNOS) expression in vascular smooth muscle cells (SMC), and other cell types such as macrophages [1][2][3]. Oxidative stress has been shown to be associated with aortic aneurysm formation in both human tissue and animal models [4][5][6]. Reactive oxygen species (ROS), including superoxide anion (O 2 − ), hydroxyl radical, and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite, are increased in human AAA [7], suggesting that ROS are one of the possible contributors to arterial wall degeneration.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model

et al. 2009

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Reactive oxygen species (ROS) are increased in human abdominal aortic aneurysms (AAA). NADPH oxidases are the predominant source of superoxide anion (O 2 − ) in the vasculature. Inducible nitric oxide synthase (iNOS) produces significant amount of nitric oxide (NO) during inflammatory processes. We hypothesized that ROS produced by NADPH oxidases and iNOS play an important role in aneurysm formation. We examined this hypothesis using selective blockade of NADPH oxidases and iNOS in a murine model of AAA. Mice, including C57BL/6, iNOS knockout (iNOS −/− ) mice, and its background matched control (C57BL/6), underwent AAA induction by periaortic application of CaCl 2 . Aortic diameter was measured at aneurysm induction and harvest. Beginning 1 week prior to aneurysm induction and continuing to aortic harvest 6 weeks later, one group of the C57BL/6 mice were treated with orally administered apocynin (NADPH oxidase inhibitor). Control mice were given water. The mean diameter and change in diameter of each group were compared with concurrent controls. Aortic levels of the NO metabolite, NO x N(NO 2 and NO 3 ), are significantly increased in CaCl 2 -treated wild type mice. INOS −/− mice are resistant to aneurysm induction. This is associated with reduced expression of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased production of NO x in the aortic tissues. Inhibition of NADPH oxidase by apocynin also blocked aneurysm formation. In conclusion, both iNOS deficiency and NADPH oxidase inhibition suppress aneurysm formation in association with decreased NO x levels. These studies suggest that both the NADPH oxidase and iNOS pathways contribute to ROS production and AAA development.

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Oxidative stress is involved in the development of experimental abdominal aortic aneurysm: A study of the transcription profile with complementary DNA microarray

Abstract: The cDNA microarray technique was useful for investigation of the transcription profiles during the development of AAA. Our results indicate that oxidative stress may play a pivotal role in the pathologic progression of AAA.

Cited by 85 publications

References 0 publications

Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms: Microarray Analysis of Surgically Resected Specimens

Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms: Microarray Analysis of Surgically Resected Specimens

Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis

Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model

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