Abstract. Lundberg GA, Kellin A, Samnegård A, Lundman P, Tornvall P, Dimmeler S, Zeiher AM, Hamsten A, Hansson GK, Eriksson P (Ö rebro University, Ö rebro and Karolinska Institute, Stockholm, Sweden; and University of Frankfurt, Frankfurt, Germany). Severity of coronary artery stenosis is associated with a polymorphism in the CXCL16/SR-PSOX gene. J Intern Med 2005; 257: 415-422.Objective. Enhanced expression of CXCL16 has been demonstrated in atherosclerotic plaques and several properties have been attributed to CXCL16 that could influence the atherosclerotic process. CXCL16 exists in transmembrane and soluble forms. The transmembrane form acts as a scavenger receptor for oxidised LDL whereas the soluble form acts a chemoattractant for mainly CD8+ T cells. In addition, the soluble form of CXCL16 influences human aortic smooth muscle cell proliferation in vitro. In the present work, a human molecular genetic approach employing a common polymorphism within exon 4 of CXCL16 (181 Ala>Val) was used to investigate whether CXCL16 may be involved in the development of coronary artery disease. The polymorphism is located within the spacer region between the chemokine and transmembrane region and potentially influences an Ala/Val cleavage site, a site commonly used for the release of chemokines by tumour necrosis factora converting enzyme. Design and subjects. We first genotyped 387 unselected survivors of a first myocardial infarction aged <60 years and 387 sex-and agematched controls. A subset of patients (n ¼ 236) was evaluated by quantitative coronary angiography. Secondly, a cohort of 468 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) with stent implantation was genotyped.Results. No significant difference in allele frequency between patient and controls of the 181 A>V polymorphism was detected. However, the V-allele was associated with increased severity of coronary stenoses. Secondly, the V-allele was associated with smaller minimal luminal diameter in the coronary segment subjected to intervention in a second cohort of patients undergoing PTCA with stent implantation. Conclusions. The present work provides evidence that CXCL16 is involved in processes leading to enhanced stenosis in atherosclerotic coronary arteries.

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Phosphatidylinositol-4-phosphate (PtdIns-P) kinase was purified approximately 30-fold from rat brain cytosol. No contaminating activity of PtdIns kinase or of phosphomonoesterase and phospholipase C using PtdIns-P or PtdIns-P2 as substrate could be detected in the enzyme preparation. The PtdIns-P kinase activity was severalfold higher when PtdIns-PIPtdEtn vesicles rather than PtdIns-P alone were used as substrate. This might be due to increased accessibility of the enzyme for the vesicular substrate, further indicated by the lower activity obtained when PtdCho or PtdIns, phospholipids with bulky head groups, was also present in the vesicles. The product PtdIns-P2 was a competitive inhibitor with respect to PtdIns-P and 50% inhibition of enzyme activity was observed at the same product concentration regardless of whether the substrate-product mixture was presented in vesicular or micellar form, or the substrate and product were added in separate vesicles.The polyamines spermine and spennidine enhanced PtdIns-P kinase activity severalfold. Spermine also caused a shift in the MgClz saturation curve from sigmoidal to hyperbolic, lowering the MgZ + concentration required for optimum kinase activity to the physiological range. Myelin basic protein enhanced the enzyme activity when PtdIns-PIPtdEtn vesicles were used as substrate, whereas it was inhibitory when PtdIns-P was added alone. The possible role of polyamines and the product PtdIns-P2 in the regulation of PtdIns-P kinase activity is discussed.According to recent hypotheses, PtdIns-Pz constitutes the substrate for a receptor-controlled phospholipase C reaction which generates diacylglycerol and inositol trisphosphate. These products then act as intracellular messengers for the activation of a protein kinase (kinase C) and for the mobilization of intracellular CaZ+, respectively [I, 21. In addition, PtdIns-P2 in the plasma membrane might play other functional roles, such as in the regulation of actin polymerization [3].

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The subcellular distribution in rat hepatocytes of enzymes participating in the entire generation cycle of phosphatidylinositol4,5bisphosphate, and phosphorylated intermediates of this pathway, has been examined by Nycodenz gradient centrifugation. Our results indicate that the synthesis of phosphatidylinositol takes place in the endoplasmic reticulum, and that its phosphorylation to phosphatidylinositol 4-phosphate occurs intracellularly in low-density membranes before translocation to the plasma membrane, where it is further phosphorylated to phosphatidylinositol4,5-bisphosphate.The intracellular formation of PIP implies a vesicular transport to the plasma membrane.