Abstract-The heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) is activated under hypoxic conditions, resulting in the upregulation of its target genes plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF). PAI-1 and VEGF are also induced in response to vascular injury, which is characterized by the activation of platelets and the coagulation cascade as well as the generation of reactive oxygen species (ROS). However, it is not known whether HIF-1 is also stimulated by thrombotic factors. We investigated the role of thrombin, platelet-associated growth factors, and ROS derived from the p22 phox -containing NADPH oxidase in the activation of HIF-1 and the induction of its target genes PAI-1 and VEGF in human vascular smooth muscle cells (VSMCs). Thrombin, platelet-derived growth factor-AB (PDGF-AB), and transforming growth factor-␤ 1 (TGF-␤ 1 ) upregulated HIF-1␣ protein in cultured and native VSMCs. This response was accompanied by nuclear accumulation of HIF-1␣ as well as by increased HIF-1 DNA-binding and reporter gene activity. The thrombin-induced expression of HIF-1␣, PAI-1, and VEGF was attenuated by antioxidant treatment as well as by transfection of p22 phox antisense oligonucleotides. Inhibition of p38 mitogen-activated protein kinase and phosphatidylinositol-3-kinase significantly decreased thrombin-induced HIF-1␣, PAI-1, and VEGF expression. These findings demonstrate that the HIF-1 signaling pathway can be stimulated by thrombin and platelet-associated growth factors and that a redox-sensitive cascade activated by ROS derived from the p22 phox -containing NADPH oxidase is crucially involved in this response. Key Words: oxygen radicals Ⅲ p22 phox Ⅲ platelets Ⅲ vascular endothelial growth factor Ⅲ plasminogen activator inhibitor-1

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Betalains are water-soluble nitrogen-containing pigments that are subdivided in red-violet betacyanins and yellow-orange betaxanthins. Due to glycosylation and acylation betalains exhibit a huge structural diversity. Betanin (betanidin-5-O-β-glucoside) is the most common betacyanin in the plant kingdom. According to the regulation on food additives betanin is permitted quantum satis as a natural red food colorant (E162). Moreover, betanin is used as colorant in cosmetics and pharmaceuticals. Recently, potential health benefits of betalains and betalain-rich foods (e.g. red beet, Opuntia sp.) have been discussed. Betanin is a scavenger of reactive oxygen species and exhibits gene-regulatory activity partly via nuclear factor (erythroid-derived 2)-like 2-(Nrf2) dependent signaling pathways. Betanin may induce phase II enzymes and antioxidant defense mechanisms. Furthermore, betanin possibly prevents LDL oxidation and DNA damage. Potential blood pressure lowering effects of red beet seem to be mainly mediated by dietary nitrate rather than by betanin per se.