Hypertension is a major risk factor for cardiovascular disease, kidney failure and stroke. Recently, increasing evidences suggest a strong association between inflammation and hypertension. On the other hand, NF kappaB is a common transcription factor involved in inflammatory response and overexpressed in different end- organ damage. The objective of this study is to examine the role of NF kappaB in hypertension. NF kappa B expression level and translocation were compared between Wistar Kyoto rat (WKY) and spontaneously hypertensive rat (SHR) kidney, heart and brain. In addition, the animals were treated with a NFkappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), for ten weeks. To determine the correlation between NF kappaB and MMP, MMP-2 and -9 activities were examined after treatment. Immunohistochemistry results showed that NF kappaB expression level is significantly increased in SHR in renal glomerular and tubulointerstitial areas and brain hypothalamus compared to that in WKY (p <0.05), but not in myocardium and cerebral cortex. Significant NF kappaB translocation into the nucleus was found in renal tubular cells, cardiac muscle cells, and arterioles of kidney and brain in SHR. After PDTC treatment, the systolic blood pressure was suppressed in SHR by 36 %. NF kappaB expression level in treated-SHR was also decreased in renal glomerular and tubulointerstitial areas and hypothalamus compared to non-treated animals (p <0.05). Also, MMP-2 and -9 activities were reduced by PDTC in SHR after treatment. The higher MMP-9 activity in SHR was also significantly decreased by PDTC (p <0.01). These results suggest NF kappaB is an important factor in hypertension and may be responsible for MMP activity

Hypoxia is linked to epithelial-mesenchymal transition (EMT) and tumor progression in numerous carcinomas. Responses to hypoxia are thought to operate via hypoxia-inducible factors (HIFs), but the importance of co-factors that regulate HIF signaling within tumors is not well understood. Here, we elucidate a signaling pathway that physically and functionally couples tyrosine phosphorylation of β-catenin to HIF1α signaling and HIF1α-mediated tumor EMT. Primary human lung adenocarcinomas accumulate pY654-β-catenin and HIF1α. All pY654-β-catenin, and only the tyrosine phosphorylated form, was found complexed with HIF1α and active Src, both within the human tumors and in lung tumor cell lines exposed to hypoxia. Phosphorylation of Y654, generated by hypoxia mediated, reactive oxygen species (ROS)-dependent Src kinase activation, was required for β-catenin to interact with HIF1α and Src, to promote HIF1α transcriptional activity, and for hypoxia-induced EMT. Mice bearing hypoxic pancreatic islet adenomas, generated by treatment with anti-vascular endothelial growth factor antibodies, accumulate HIF1α/pY654-β-catenin complexes and develop an invasive phenotype. Concurrent administration of the ROS inhibitor N-acetylcysteine abrogated β-catenin/HIF pathway activity and restored adenoma architecture. Collectively, the findings implicate accumulation of pY654-β-catenin specifically complexed to HIF1α and Src kinase as critically involved in HIF1α signaling and tumor invasion. The findings also suggest that targeting ROS-dependent aspects of the pY654-β-catenin/ HIF1α pathway may attenuate untoward biological effects of anti-angiogenic agents and tumor hypoxia.