Our data indicate that oxLDL-induced dephosphorylation of Akt, followed by impaired eNOS activation, reduces the intracellular level of NO and thereby inhibits VEGF-induced EC migration.

The renin-angiotensin system (RAS) is involved in the pathogenesis of essential hypertension. In the present study we examined the genotype frequencies of the insertion/deletion polymorphisms of the ACE gene and the M235T polymorphism of the Angiotensinogen (Agt) gene in patients with essential hypertension in comparison with normotensive subjects. In hypertensive patients functional effects of blood pressure response to ACE inhibition were investigated. A total of 121 patients with essential hypertension (group 1) and 125 normotensive control subjects (group 2) were included in this study. All patients were genotyped by polymerase chain reactions (PCR) for the insertion/deletion (I/D) polymorphism of the ACE gene and the M235T polymorphism of the Agt gene. To analyze possible functional impacts on blood pressure regulation 50 mg of captopril was administered to hypertensive patients. No significant association of essential hypertension with polymorphisms of the Agt and ACE gene was found. The ACE serum levels in patients with the DD-genotype of the ACE I/D polymorphism were higher than in patients with the II-genotype (P < .01). In patients with the ID-genotype the ACE serum levels were in-between. A captopril test was performed in hypertensive patients. The patients were further divided into subgroups according to the diastolic and systolic blood pressure response. Group 1a consisted of patients with a diastolic blood pressure drop of > 5 mm Hg and group 1b with < or =5 mm Hg. Group 1c consisted of patients with a systolic blood pressure drop of > 10 mm Hg and group 1d with < or =10 mm Hg. Twice as many patients with the DD genotype of the ACE gene were found in group 1a compared to group 1b (chi(2) = 5.673; P = .017). No association of systolic blood pressure change to the investigated polymorphisms was found. Our results do not support the hypothesis that the investigated polymorphisms contribute to essential hypertension. Furthermore, no major impact of these polymorphisms on blood pressure response to captopril were detected. We conclude that the investigated genotypes have no influence on blood pressure level and homeostasis.

In mesangial cells angiotensin II (Ang II) has been shown to activate extracellular regulated kinases 1 and 2 (ERK1/ 2). Here, we studied the role of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) in Ang II-induced ERK1/2 activation in human mesangial cells. Ang II induced activation of ERK1/2 via the AT 1 receptor, and this response was blocked by the PDGFRselective tyrosine kinase inhibitor AG1295, but not by AG1478, an EGFR-selective tyrosine kinase inhibitor, indicating participation of the PDGFR, but not of the EGFR in Ang II-induced ERK1/2 activation. In agreement with this assumption, Ang II caused tyrosine phosphorylation of the PDGFR and the adapter protein Shc in an AG1295-sensitive fashion. In conclusion, our data show that Ang II-induced activation of mitogenic signalling cascade in human mesangial cells involves ligand-independent activation of the PDGFR, but not of the coexpressed EGFR.z 2000 Federation of European Biochemical Societies.

Given the important role of cAMP in cell proliferation (1), we initially studied the effect of membrane-permeable Epac-selective and non-selective cAMP analogs on cell proliferation. We found that 8-pCPT-substituted cAMP analogs as well as their potential hydrolysis products strongly inhibit The transport of nucleosides into mammalian cells is accomplished by two types of transporters: concentrative nucleoside transporters, which use the Na ϩ gradient to actively transport nucleosides into the cells, and equilibrative nucleoside transporters (ENTs), which transport nucleosides in both directions and toward equal intra-and extracellular adenosine concentration (8, 9). ENTs play key roles in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis and are also responsible for the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases. By regulating the concentration of adenosine available to ubiquitously expressed cell surface adenosine receptors, nucleoside transporters appear to play important regulatory roles in many physiological * This work was supported by grants from the Deutsche Forschungsgemeinschaft (Grant Pi 258/7-4) and in part by grants from the University of Saarland (HOMFOR), the Wilhelm Sander foundation (Grant 2003.119.2), and the Marie Christine Held and Erika Hecker foundation.

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