The heme moiety of denatured hemoproteins (heme-proteins) is degraded by HO-1 &HO-2, to CO and biliverdin (BV), an HO activity inhibitor;BV is reduced by its reductase (BVR) to the antioxidant, bilirubin. CO has anti-inflammatory and vasodilatory activities. Stimuli that cause oxidative stress and hemoprotein denaturation, such as surgical interventions, inherited and transmitted hemolytic diseases, and certain drugs, industrial and environmental agents, induce ho-1. The kidney tubules are the target of potent pro-oxidant activity of heme-compounds. To date, no effective strategy has been described to counter heme-protein renal toxicity;however, increase in HO-1 activity by activation of stress-activated response elements, e.g., AP-1/CRE, AREs (antioxidant response elements) is considered cytoprotective. The activation involves cell-line independent binding of basic leucine zipper (bZip) transcription factors: c-Jun, ATF- 2/CREB, and Nrf2. The MAPK and PI3-K pathways transduce signals for activation of bZip factors and """"""""cross talk"""""""" using PKCs. bZip factor activity is subject to the identity of its dimeric partner. Phosphorylation of the ultimate target gene product, e.g., HO-1, alters its activity and turnover. In vitro and in cultured cells, we have discovered that: the human (h) BVR is one of the rare kinases that control MAPK and PI3-K signaling;is a bZip factor;activated by ho-1 inducers;and, traffics between the cytosol and nucleus. hBVR binds to AP-l/CRE and ARE elements and also enhances ATF-2 and Nrf2 binding to AP-1 and/or ARE;promotes induction and activation of ATF-2, c-Jun and c-Fos;activates kinase mediators of ho-1 response, i.e. PKCs and PKB/Akt;and, causes cell differentiation. BVR regulates ho-1 oxidative stress response and its anti-apoptotic effect. The overall objective of this application is to further investigate regulation of HO-1 activity by BVR at the molecular and cellular levels and to extend the investigation to the intact animal.
Specific aims are to examine: i) function of BVR as kinase:kinase in phosphorylation, activity, and turnover of HO-1;2) the role of hBVR in transcriptional activity of ATF-2 and Nrf2;and, 3) whether increased levels of BVR protect against heme-mediated injury. Mice expressing hBVR in renal tubules and treated with the hemolytic agent, phenylhydrazine, will be analyzed for pathophysiology, antioxidant status, kinase activities and HO-1 levels. Liver will serve as the non-target organ as control for the expression of the transgene.
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