Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Systemic Administration of Heparin Intraoperatively in Patients Undergoing Open Repair of Leaking Abdominal Aortic Aneurysm May Be Beneficial and Does Not Cause Problems

The aim of this study was to investigate whether intravenous heparin administration was associated with a reduction in perioperative mortality and late distal thrombectomy in patients with ruptured abdominal aortic aneuryms (AAAs). One hundred thirty-one patients had repair of ruptured AAA between January 1999 and January 2004. Sixty-three received heparin according to the consultant's preference at the time of the operation. Data were prospectively collected, and multivariate analysis was performed for independent predictive factors. Thirty-day mortality was 29%. Patients receiving heparin had lower perioperative mortality (16% vs 42%; p = .001). Heparin administration was not associated with increased hemorrhage or transfusion. Multivariate analysis confirmed that heparin administration was independently predictive of survival ( p = .036). Other factors found to reduce survival were age ( p = .023), smoking ( p = .042), and systolic blood pressure (&lt; 100 mmHg) at presentation ( p = .045). Fewer patients had thrombectomy after heparin (8% vs 12%), but this was not statistically significant. Perioperative complications were similar in both groups. The administration of systemic heparin before the clamp is applied to leaking aneurysms does not appear to increase hemorrhage and subsequent mortality and may reduce the need for early thrombectomy. </jats:p

Detection and cellular localization of heparin-binding epidermal growth factor-like growth factor mRNA and protein in human atherosclerotic tissue

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family which binds to and activates the epidermal growth factor (EGF) receptor. HB-EGF mRNA is expressed by monocytes and vascular smooth muscle cells (VSMC) in culture, and has been shown to be a potent VSMC mitogenin vitro. The aim of this study was to screen normal and human atherosclerotic arteries and SMC cultured from these arteries for expression of HB-EGF, and to determine its cellular localization in human lesions. Using the highly sensitive technique of reverse transcription polymerase chain reaction (RT-PCR), we screened biopsies taken from normal human vessel walls and atherosclerotic tissue, for expression of HB-EGF mRNA. Northern blotting and RT-PCR were employed to determine levels of HB-EGF gene expression in SMC, cultured from normal and atherosclerotic arteries. Cellular localization of mRNA and protein, within human atherosclerotic plaques, was assessed using in situ hybridization with 35S labelled riboprobes, and immunohistochemistry with polyclonal antibodies specific for human HB-EGF. HB-EGF mRNA was found to be expressed in human atherosclerotic lesions and in VSMC cultured from these lesions. Expression of HB-EGF could not be detected in quiescent aortic VSMC using Northern blotting, but was highly up-regulated in these cells after treatment with basic fibroblast growth factor (bFGF) for 24 h. Although HB-EGF mRNA was detected in all vascular tissue examined using RT-PCR, in situ hybridization and immunohistochemistry revealed expression of HB-EGF in small portions of diseased arteries only. Immunohistochemistry showed strong staining for macrophages in all areas of HB-EGF expression. No association of HB-EGF with SMC was observed in any of the specimens examined. In conclusion, HB-EGF, a potent mitogen for VSMC, is expressed by macrophages in human atherosclerotic arteries, suggesting a role for the growth factor in the development of atherosclerotic plaques

Human tribbles homologue 2 is expressed in unstable regions of carotid plaques and regulates macrophage IL-10 in vitro

International audienceMammalian orthologs of the Drosophila tribbles protein (Trb1, Trb2 and Trb3) are a recently described family of signalling molecules that regulate gene expression by modulation of protein kinase signalling pathways. In this study, a screen for mRNA species specifically regulated in vulnerable regions of human atherosclerotic plaque demonstrated upregulation of both Trb1 and Trb2, the latter by more than 8-fold. In vitro experiments in primary human monocyte-derived macrophages showed that Trb2 expression was upregulated by treatment with oxidised low density lipoprotein (LDL), and that expression of recombinant Trb2 specifically reduced macrophage levels of IL-10 mRNA. Our results thus identify Trb2 as a highly regulated gene in vulnerable atherosclerotic lesions, and demonstrate inhibition of macrophage IL-10 biosynthesis as a potential pro-inflammatory consequence of high Trb2 expression that may contribute to plaque instability

Hematopoietic Progenitor Cells and Restenosis After Carotid Endarterectomy

Background and Purpose— Hematopoietic progenitor cells (HPCs) may attenuate the response to vascular injury by maintaining endothelial integrity and function. Our aim was to determine whether circulating HPC number and function correlate with restenosis after carotid endarterectomy. Methods— HPC number (CD34 + /CD133 + cells), early colony-forming units, migratory capacity, and senescence were analyzed in blood collected preoperatively, 1 day, and 6 weeks postoperatively. Mobilizing cytokine levels were also measured. Stenosis was assessed by duplex scanning. Results— HPC numbers ( P &lt;0.001) and early colony-forming unit count ( P =0.001) fell rapidly 24 hours postoperatively. Restenosis at 6 months correlated negatively with the magnitude of postoperative falls in HPC numbers ( R =−0.38, P =0.013) and early colony-forming unit counts ( R =−0.42, P =0.008). The migratory capacity of preoperative HPCs correlated negatively with restenosis ( R =−0.48, P =0.007). Preoperative SDF1 levels correlated with falls in HPC number ( R =0.42, P =0.044) and early colony-forming unit counts ( R =0.56, P =0.004). Conclusions— HPC function appears to be linked to the development of carotid artery restenosis after endarterectomy. These data support the concept that HPCs have a role in regulating remodeling of the injured arterial wall. </jats:sec