Publications

Paraoxonase is a high-density-lipoprotein-associated enzyme capable of hydrolysing lipid peroxides. Thus it might protect lipoproteins from oxidation. It has two isoforms, which arise from a glutamine (A isoform) to arginine (B isoform) interchange at position 192. The relevance of this polymorphism to coronary heart disease (CHD) in non-insulin-dependent diabetic patients was investigated in case-control study. Of the 434 patients, 171 had confirmed coronary artery disease; the other 263 had no history of such disease. The B allele and AB+BB genotypes were associated with an increased risk of coronary heart disease. Compared with subjects homozygous for the A allele (AA genotype), the odds ratio of CHD for subjects homozygous for the B allele was 2.5 (95% CI 1.2-5.3) and that for those heterozygous for the B allele was 1.6 (95% CI 1.1-2.4), suggesting a codominant effect on cardiovascular risk. When subjected to multivariate analysis, the B allele remained significantly associated with CHD (odds ratio 1.94, p = 0.03). The paraoxonase gene polymorphism is thus an independent cardiovascular risk factor in non-insulin-dependent diabetic patients. A possible explanation for this finding is that activity of the paraoxonase B isotype does not protect well against lipid oxidation, a major atherogenic pathway.

The integrin family of adhesion receptors consists of at least 21 heterodimeric transmembrane proteins that differ in their tissue distribution and ligand specificity. The recently identified alpha 8 integrin subunit associates with beta 1 and is predominantly expressed in smooth muscle and other contractile cells in adult tissues, and in mesenchymal and neural cells during development. We now show that alpha 8 beta 1 specifically localizes to focal contacts in cells plated on the extracellular matrix proteins fibronectin or vitronectin. In addition we show that human embryonic kidney cells (293), transfected with alpha 8 cDNA, express alpha 8 beta 1 on their surface and use this receptor for adhesion to fibronectin and vitronectin. Furthermore, alpha 8 beta 1 binds to both fibronectin- and vitronectin-Sepharose and can be specifically eluted from either matrix protein by the arginine-glycine-aspartic acid (RGD)-containing peptide, GRGDSP. Because fibronectin and vitronectin adhesion appeared to be mediated by RGD, we examined additional RGD-containing proteins, including tenascin, fibrinogen, thrombospondin, osteopontin, and denatured collagen type I. We found that only tenascin was able to mediate adhesion of alpha 8-transfected 293 cells. By using recombinant fragments of tenascin in adhesion assays, we were able to localize the alpha 8 beta 1 binding domain of tenascin to the RGD-containing third fibronectin type III repeat. These data strongly suggest that tenascin, fibronectin, and vitronectin are ligands for alpha 8 beta 1 and that this integrin binds to the RGD site in each of these ligands through mechanisms that are distinct and separate from alpha 5- and alpha v-containing integrins.