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Abstract: Autotaxin (ATX) is a secreted lysophospholipase D that generates the multifunctional lipid mediator lysophosphatidic acid (LPA). LPA signals through six distinct G protein-coupled receptors, acting alone or in concert to activate multiple effector pathways. The ATX–LPA signaling axis is implicated in a remarkably wide variety of physiological and pathological processes and plays a vital role in embryonic development. Disruption of the ATX-encoding gene (Enpp2) in mice results in intrauterine death due to vascular defects in the extra-embryonic yolk sac and embryo proper. In addition, Enpp2 (−/−) embryos show impaired neural development. The observed angiogenic defects are attributable, at least in part, to loss of LPA signaling through the Gα12/13-linked RhoA-ROCK-actin remodeling pathway. Studies in zebrafish also have uncovered a dual role for ATX in both vascular and neural development; furthermore, they point to a key role for ATX–LPA signaling in the regulation of left–right asymmetry. Here we discuss our present understanding of the role of ATX–LPA signaling in vertebrate development. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. [Copyright &y& Elsevier]

Abstract: A new variant of the HLA-A*010101 allele designated as HLA-A*0111N, previously known as HLA-A*010101var, was identified in a patient requiring a stem-cell transplantation. The patient was typed by serologic methods as HLA-A2 homozygous and by sequence-based typing (SBT) as A*010101,020601. Flow-cytometric (FCM) analysis with 11 human monoclonal antibodies (mAbs) for the A1 molecule confirmed lack of any cell membrane expression of the A*0111N allele. One-dimensional isoelectric focusing (1D-IEF) of total cell lysate from the patient’s cells revealed no cell surface and cytoplasmic A1 protein expression, whereas the HLA-A2 molecule was identified by both FCM analysis and 1D-IEF. DNA sequence analysis showed the presence of a synonymous substitution from G to T at position 597 in codon 175. RNA SBT revealed a deletion of 24 bp in exon 3, position 596 through 619, encoding codons 175 through 182 of the HLA-A*0111N allele. The synonymous substitution introduced a new splice site, resulting in an efficient splicing, because no classical A1 protein could be detected in the patient. This alternative splicing prevented the translation into a correct and stable class I molecule expression on the cell surface. [Copyright &y& Elsevier]

Abstract: Objective: Angiogenesis and inflammation are important features in atherosclerotic plaque destabilization. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulator of angiogenesis and is also involved in inflammatory reactions. We studied HIF-1α expression in different atherosclerotic plaque phenotypes. Methods and results: HIF-1α expression was observed in 18/37 (49%) carotid and in 9/15 (60%) femoral endarterectomy specimens. Expression of HIF-1α was associated with the presence of a large extracellular lipid core (P =0.03) and macrophages (P =0.02). HIF-1α co-localized with vascular endothelial growth factor (VEGF), an important downstream target of HIF-1α. In addition, a strong association was observed between expression levels of HIF-1α and VEGF (P =0.001). The average number of plaque microvessels was higher in plaques with no or minor HIF-1α staining than in plaques with moderate or heavy HIF-1α staining (P =0.03). In human macrophages, lipopolysaccharide activation induced HIF-1α expression. In embryonic fibroblasts derived from wild-type mice, lipopolysaccharide activation induced an increase in HIF-1α mRNA, whereas in Toll-like receptor 4 defective embryonic fibroblasts no effect was observed after lipopolysaccharide stimulation. Conclusions: In atherosclerotic plaque, the transcription factor HIF-1α is associated with an atheromatous inflammatory plaque phenotype and with VEGF expression. HIF-1α expression is upregulated in activated macrophages under normoxic conditions. [Copyright &y& Elsevier]