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Peripheral arterial occlusive disease: global gene expression analyses suggest a major role for immune and inflammatory responses.

Fu S, Zhao H, Shi J, Abzhanov A, Crawford K, Ohno-Machado L, Zhou J, Du Y, Kuo WP, Zhang J, Jiang M, Jin JG - BMC Genomics (2008)

Bottom Line: Under a stringent cutoff, i.e., a false discovery rate (FDR) <0.5%, we found 366 genes were differentially regulated in intermediate lesions and 447 in advanced lesions.In these differentially regulated genes, immune/inflammatory genes were significantly up-regulated in different stages of PAD, (85/230 in intermediate lesions, 37/172 in advanced lesions).Further studies of these signature molecules may eventually allow us to develop more sophisticated protocols for pharmaceutical interventions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. sjfu@sibs.ac.cn

ABSTRACT

Background: Peripheral arterial disease (PAD), a major manifestation of atherosclerosis, is associated with significant cardiovascular morbidity, limb loss and death. However, mechanisms underlying the genesis and progression of the disease are far from clear. Genome-wide gene expression profiling of clinical samples may represent an effective approach to gain relevant information.

Results: After histological classification, a total of 30 femoral artery samples, including 11 intermediate lesions, 14 advanced lesions and 5 normal femoral arteries, were profiled using Affymetrix microarray platform. Following real-time RT-PCR validation, different algorithms of gene selection and clustering were applied to identify differentially expressed genes. Under a stringent cutoff, i.e., a false discovery rate (FDR) <0.5%, we found 366 genes were differentially regulated in intermediate lesions and 447 in advanced lesions. Of these, 116 genes were overlapped between intermediate and advanced lesions, including 68 up-regulated genes and 48 down-regulated ones. In these differentially regulated genes, immune/inflammatory genes were significantly up-regulated in different stages of PAD, (85/230 in intermediate lesions, 37/172 in advanced lesions). Through literature mining and pathway analysis using different databases such as Gene Ontology (GO), and the Kyoto Encyclopedia of Gene and Genomics (KEGG), genes involved in immune/inflammatory responses were significantly enriched in up-regulated genes at different stages of PAD(p < 0.05), revealing a significant correlation between immune/inflammatory responses and disease progression. Moreover, immune-related pathways such as Toll-like receptor signaling and natural killer cell mediated cytotoxicity were particularly enriched in intermediate and advanced lesions (P < 0.05), highlighting their pathogenic significance during disease progression.

Conclusion: Lines of evidence revealed in this study not only support previous hypotheses, primarily based on studies of animal models and other types of arterial disease, that inflammatory responses may influence the development of PAD, but also permit the recognition of a wide spectrum of immune/inflammatory genes that can serve as signatures for disease progression in PAD. Further studies of these signature molecules may eventually allow us to develop more sophisticated protocols for pharmaceutical interventions.

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Over-representation of Toll-like receptor signaling pathway genes. Analysis of over-representation of differentially expressed genes in pathway from KEGG. The Toll-like receptor signaling pathway is illustrated with significantly regulated genes highlighted.
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Figure 8: Over-representation of Toll-like receptor signaling pathway genes. Analysis of over-representation of differentially expressed genes in pathway from KEGG. The Toll-like receptor signaling pathway is illustrated with significantly regulated genes highlighted.

Mentions: A pathway analysis database, KEGG, was then applied to genes differentially regulated in intermediate and advanced lesions. Several overrepresented pathways were identified, and the enriched pathways appeared not to be independent of one another, many genes involved in one pathway could be also involved in another pathway. This interaction is illustrated in Figure 7, and pathway abbreviations can be found in Table 5. As demonstrated, many immune-related pathways were significantly over-represented in intermediate and/or advanced lesions including TLR, NK, BCR, FER, APP, CCC and LTEM pathways. These findings, on the one hand, provide evidence supporting previous hypotheses that immune/inflammatory responses play important roles in the development of PAD, and on the other hand, demonstrate that particular components of immune/inflammatory systems can be crucial for the genesis and progression of PAD. For instance, TLR and NK pathways are shown to be particularly overrepresented in both intermediate lesions and advanced lesions, highlighting their functional importance in the disease. The TLR pathway is shown in Figure 8 with the differentially regulated genes indicated.


Peripheral arterial occlusive disease: global gene expression analyses suggest a major role for immune and inflammatory responses.

Fu S, Zhao H, Shi J, Abzhanov A, Crawford K, Ohno-Machado L, Zhou J, Du Y, Kuo WP, Zhang J, Jiang M, Jin JG - BMC Genomics (2008)

Over-representation of Toll-like receptor signaling pathway genes. Analysis of over-representation of differentially expressed genes in pathway from KEGG. The Toll-like receptor signaling pathway is illustrated with significantly regulated genes highlighted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2529314&req=5

Figure 8: Over-representation of Toll-like receptor signaling pathway genes. Analysis of over-representation of differentially expressed genes in pathway from KEGG. The Toll-like receptor signaling pathway is illustrated with significantly regulated genes highlighted.
Mentions: A pathway analysis database, KEGG, was then applied to genes differentially regulated in intermediate and advanced lesions. Several overrepresented pathways were identified, and the enriched pathways appeared not to be independent of one another, many genes involved in one pathway could be also involved in another pathway. This interaction is illustrated in Figure 7, and pathway abbreviations can be found in Table 5. As demonstrated, many immune-related pathways were significantly over-represented in intermediate and/or advanced lesions including TLR, NK, BCR, FER, APP, CCC and LTEM pathways. These findings, on the one hand, provide evidence supporting previous hypotheses that immune/inflammatory responses play important roles in the development of PAD, and on the other hand, demonstrate that particular components of immune/inflammatory systems can be crucial for the genesis and progression of PAD. For instance, TLR and NK pathways are shown to be particularly overrepresented in both intermediate lesions and advanced lesions, highlighting their functional importance in the disease. The TLR pathway is shown in Figure 8 with the differentially regulated genes indicated.

Bottom Line: Under a stringent cutoff, i.e., a false discovery rate (FDR) <0.5%, we found 366 genes were differentially regulated in intermediate lesions and 447 in advanced lesions.In these differentially regulated genes, immune/inflammatory genes were significantly up-regulated in different stages of PAD, (85/230 in intermediate lesions, 37/172 in advanced lesions).Further studies of these signature molecules may eventually allow us to develop more sophisticated protocols for pharmaceutical interventions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. sjfu@sibs.ac.cn

ABSTRACT

Background: Peripheral arterial disease (PAD), a major manifestation of atherosclerosis, is associated with significant cardiovascular morbidity, limb loss and death. However, mechanisms underlying the genesis and progression of the disease are far from clear. Genome-wide gene expression profiling of clinical samples may represent an effective approach to gain relevant information.

Results: After histological classification, a total of 30 femoral artery samples, including 11 intermediate lesions, 14 advanced lesions and 5 normal femoral arteries, were profiled using Affymetrix microarray platform. Following real-time RT-PCR validation, different algorithms of gene selection and clustering were applied to identify differentially expressed genes. Under a stringent cutoff, i.e., a false discovery rate (FDR) <0.5%, we found 366 genes were differentially regulated in intermediate lesions and 447 in advanced lesions. Of these, 116 genes were overlapped between intermediate and advanced lesions, including 68 up-regulated genes and 48 down-regulated ones. In these differentially regulated genes, immune/inflammatory genes were significantly up-regulated in different stages of PAD, (85/230 in intermediate lesions, 37/172 in advanced lesions). Through literature mining and pathway analysis using different databases such as Gene Ontology (GO), and the Kyoto Encyclopedia of Gene and Genomics (KEGG), genes involved in immune/inflammatory responses were significantly enriched in up-regulated genes at different stages of PAD(p < 0.05), revealing a significant correlation between immune/inflammatory responses and disease progression. Moreover, immune-related pathways such as Toll-like receptor signaling and natural killer cell mediated cytotoxicity were particularly enriched in intermediate and advanced lesions (P < 0.05), highlighting their pathogenic significance during disease progression.

Conclusion: Lines of evidence revealed in this study not only support previous hypotheses, primarily based on studies of animal models and other types of arterial disease, that inflammatory responses may influence the development of PAD, but also permit the recognition of a wide spectrum of immune/inflammatory genes that can serve as signatures for disease progression in PAD. Further studies of these signature molecules may eventually allow us to develop more sophisticated protocols for pharmaceutical interventions.

Show MeSH
Related in: MedlinePlus