Novel Pathways in the Pathobiology of Human Abdominal Aortic Aneurysms

Objectives: Abdominal aortic aneurysm (AAA), a dilatation of the infrarenal aorta, typically affects males >65 years. The pathobiological mechanisms of human AAA are poorly understood. The goal of this study was to identify novel pathways involved in the development of AAAs. Methods: A custom-designed ‘AAA-chip’ was used to assay 43 of the differentially expressed genes identified in a previously published microarray study between AAA (n = 15) and control (n = 15) infrarenal abdominal aorta. Protein analyses were performed on selected genes. Results: Altogether 38 of the 43 genes on the ‘AAA-chip’ showed significantly different expression. Novel validated genes in AAA pathobiology included ADCY7, ARL4C, BLNK, FOSB, GATM, LYZ, MFGE8, PRUNE2, PTPRC, SMTN, TMODI and TPM2. These genes represent a wide range of biological functions, such as calcium signaling, development and differentiation, as well as cell adhesion not previously implicated in AAA pathobiology. Protein analyses for GATM, CD4, CXCR4, BLNK, PLEK, LYZ, FOSB, DUSP6, ITGA5 and PTPRC confirmed the mRNA findings. Conclusion: The results provide new directions for future research into AAA pathogenesis to study the role of novel genes confirmed here. New treatments and diagnostic tools for AAA could potentially be identified by studying these novel pathways.

[1]  H. Kuivaniemi,et al.  Presence of Borrelia burgdorferi sensu lato antibodies in the serum of patients with abdominal aortic aneurysms , 2011, European Journal of Clinical Microbiology & Infectious Diseases.

[2]  Benjamin F. J. Verhaaren,et al.  The pathophysiology of abdominal aortic aneurysm growth: corresponding and discordant inflammatory and proteolytic processes in abdominal aortic and popliteal artery aneurysms. , 2010, Journal of vascular surgery.

[3]  M. Piechota,et al.  Gene Expression Profiles in Human Ruptured and Unruptured Intracranial Aneurysms: What Is the Role of Inflammation? , 2010, Stroke.

[4]  S. Bouyain,et al.  The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules , 2010, Proceedings of the National Academy of Sciences.

[5]  B. Giusti,et al.  Gene expression profiling of peripheral blood in patients with abdominal aortic aneurysm. , 2009, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[6]  A. Boddy,et al.  Identification of a genetic variant associated with abdominal aortic aneurysms on chromosome 3p12.3 by genome wide association , 2009 .

[7]  N. Jafari,et al.  Genomics of Human Intracranial Aneurysm Wall , 2009, Stroke.

[8]  E. Choke,et al.  Whole genome-expression profiling reveals a role for immune and inflammatory response in abdominal aortic aneurysm rupture. , 2009, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[9]  Satoko Nakamura,et al.  Renal Artery Stenosis and Renal Parenchymal Damage in Patients with Abdominal Aortic Aneurysm Proven by Autopsy , 2009, Kidney and Blood Pressure Research.

[10]  D. Barrell,et al.  Nucleic Acids Research Advance Access published October 27, 2008 The GOA database in 2009—an integrated Gene Ontology Annotation resource , 2008 .

[11]  E. Ocaña,et al.  Chemokine receptor expression on infiltrating lymphocytes from abdominal aortic aneurysms: role of CXCR4-CXCL12 in lymphoid recruitment. , 2008, Atherosclerosis.

[12]  P. Doevendans,et al.  Smoothelin-B Deficiency Results in Reduced Arterial Contractility, Hypertension, and Cardiac Hypertrophy in Mice , 2008, Circulation.

[13]  A. Boddy,et al.  Basic research studies to understand aneurysm disease. , 2008, Drug news & perspectives.

[14]  I. Benjamin,et al.  CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice. , 2007, American journal of physiology. Heart and circulatory physiology.

[15]  H. Okamoto,et al.  Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice , 2007, Proceedings of the National Academy of Sciences.

[16]  L. Alfredsson,et al.  A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity , 2007, Arthritis research & therapy.

[17]  Gerard Tromp,et al.  Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms , 2007, BMC Genomics.

[18]  T. Akata.  Cellular and molecular mechanisms regulating vascular tone. Part 2: regulatory mechanisms modulating Ca2+ mobilization and/or myofilament Ca2+ sensitivity in vascular smooth muscle cells , 2007, Journal of Anesthesia.

[19]  Alberto Mantovani,et al.  Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression1 , 2006, The Journal of Immunology.

[20]  M. Yacoub,et al.  Myocardial Expression of the Arginine:Glycine Amidinotransferase Gene Is Elevated in Heart Failure and Normalized After Recovery: Potential Implications for Local Creatine Synthesis , 2006, Circulation.

[21]  S. Dasgupta,et al.  Lactadherin binding and phosphatidylserine expression on cell surface-comparison with annexin A5. , 2006, Translational research : the journal of laboratory and clinical medicine.

[22]  G. Fraedrich,et al.  High Prevalence of Circulating CD4+CD28− T-Cells in Patients With Small Abdominal Aortic Aneurysms , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[23]  GustavFraedrich,et al.  High Prevalence of Circulating CD4+CD28− T-Cells in Patients With Small Abdominal Aortic Aneurysms , 2005 .

[24]  S. Bykov,et al.  A soluble C1b protein and its regulation of soluble type 7 adenylyl cyclase. , 2004, Biochemistry.

[25]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[26]  R. Berguer,et al.  Elevated Expression of Matrix Metalloproteinase-13 in Abdominal Aortic Aneurysms , 2004, Annals of vascular surgery.

[27]  S. Nagata,et al.  Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice , 2004, Science.

[28]  Stephen W. K. Cheng,et al.  Differential expression of integrin α5β1 in human abdominal aortic aneurysm and healthy aortic tissues and its significance in pathogenesis , 2004 .

[29]  T. Greiner,et al.  Key Roles of CD4+ T Cells and IFN-γ in the Development of Abdominal Aortic Aneurysms in a Murine Model1 , 2004, The Journal of Immunology.

[30]  I. Olsen,et al.  Multiple bacteria in aortic aneurysms. , 2003, Journal of vascular surgery.

[31]  L. Tessarollo,et al.  Neural crest stem cell and cardiac endothelium defects in the TrkC null mouse , 2003, Molecular and Cellular Neuroscience.

[32]  J. Weitzman,et al.  A role for AP-1 in apoptosis: the case for and against. , 2003, Biochimie.

[33]  P. Krammer,et al.  An unexpected role for FosB in activation-induced cell death of T cells , 2003, Oncogene.

[34]  H. Leonhardt,et al.  Identification and Characterization of Novel Smoothelin Isoforms in Vascular Smooth Muscle , 2001, Journal of Vascular Research.

[35]  O. Levy,et al.  Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein. , 1999 .

[36]  F. Ramaekers,et al.  Smoothelin in adult and developing human arteries and myocardium , 1999, Histochemistry and Cell Biology.

[37]  S. Steinbacher,et al.  Crystal structure and mechanism of human L‐arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis , 1998, The EMBO journal.

[38]  E. Haber,et al.  Molecular Cloning and Characterization of SmLIM, a Developmentally Regulated LIM Protein Preferentially Expressed in Aortic Smooth Muscle Cells (*) , 1996, The Journal of Biological Chemistry.

[39]  J. Sikela,et al.  Localization of the gene for a novel human adenylyl cyclase (ADCY7) to chromosome 16 , 1995, Human Genetics.

[40]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[41]  Stephen W. K. Cheng,et al.  Differential expression of integrin alpha5beta1 in human abdominal aortic aneurysm and healthy aortic tissues and its significance in pathogenesis. , 2004, The Journal of surgical research.

[42]  O. Topolcan,et al.  Inflammation in the wall of abdominal aortic aneurysm and its role in the symptomatology of aneurysm. , 2002, Cytokines, cellular & molecular therapy.

[43]  L. A. Anderson.  Abdominal aortic aneurysm. , 2001, The Journal of cardiovascular nursing.

[44]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..