Binding sites for ETS family of transcription factors dominate the promoter regions of differentially expressed genes in abdominal aortic aneurysms.

BACKGROUND: Previously, we identified 3274 distinct differentially expressed genes in abdominal aortic aneurysm (AAA) tissue compared with nonaneurysmal controls. As transcriptional control is responsible for these expression changes, we sought to find common transcriptional elements in the promoter regions of the differentially expressed genes. METHODS AND RESULTS: We analyzed the up- and downregulated gene sets with Whole Genome rVISTA to determine the transcription factor (TF) binding sites overrepresented in the 5-kb promoter regions of the 3274 genes. The downregulated gene set yielded 144 TF binding sites that were overrepresented in the subset when compared with the entire genome. In contrast, the upregulated gene set yielded only 13 distinct overrepresented TF binding sites. Interestingly, as classified by TRANSFAC, 8 of the 13 TFs binding to these regions belong to the ETS family. Additionally, nuclear factor kB and its subunits p50 and p65 showed enrichment. Immunohistochemical analyses of 10 TFs from the upregulated set showed 9 to be present in AAA tissue. Based on gene ontology analysis of biological process categories of the upregulated target genes of enriched TFs, 10 TFs had enrichment in immune system process among their target genes. CONCLUSIONS: Our genome-wide analysis provides further evidence of ETS and nuclear factor kB involvement in AAA. Additionally, our results provide novel insight for future studies aiming to dissect the pathogenesis of AAA and have uncovered potential therapeutic targets for AAA prevention.

Basic research studies to understand aneurysm disease.

Abdominal aortic aneurysm (AAA) is a complex multifactorial disease with life-threatening implications. Aneurysms typically have no signs or symptoms, and rupture of AAA has a high mortality rate. Multiple environmental and genetic risk factors are involved in aneurysm formation and progression making it a complicated disease to study. Little is understood about the mechanisms in disease initiation, thus there are currently no therapeutic approaches to prevent AAA, leaving patients with surgery as their only option. Ongoing research into the genetic components of AAA using a candidate gene approach has been overall unsuccessful. A more promising approach to study complex diseases involves genome-wide techniques such as DNA linkage analysis, genetic association studies and microarray expression profiling. Furthermore, studies involving inhibition of AAA progression, rather than formation, have a potentially promising outcome. Targeting biological pathways in AAA pathogenesis may benefit patients by slowing the growth and possibly preventing the rupture of AAA. Critical pathways involved in AAA pathogenesis include immunological processes, such as T-cell and natural killer cell pathways, oxidative stress, depletion of vascular smooth muscle cells through the process of apoptosis and the destruction of the extracellular matrix by matrix metalloproteinases.