Peripheral arterial occlusive disease: Global gene expression analyses suggest a major role for immune and inflammatory responses
1 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
2 Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
3 Laboratory for Innovative Translational Technologies, Harvard School of Dental Medicine, Boston, MA, USA
4 ShanghaiBio Corporation, 675 US Highway One, North Brunswick, NJ, USA
5 Shanghai Biochip Co., Ltd and National Engineering Center for Biochip at Shanghai, Shanghai, PR China
6 Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA
7 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
8 Decision Systems Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
9 Department of Orthopedics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
10 School of Pharmacy, Soochow University, Suzhou, JiangSu, PR China
11 Graduate School of the Chinese Academy of Sciences, Shanghai, PR China
BMC Genomics 2008, 9:369 doi:10.1186/1471-2164-9-369Published: 1 August 2008
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.
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.
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.