It has become increasingly apparent that NO induces a number of adaptive responses in vascular cells which may protect and enhance the survival of these cells. The mechanisms are not clear, however, NO has been shown by us and others to increase expression of HO-1, HSP-70 and increase cellular levels GSH levels in smooth muscle and endothelial cells. In each case these responses are associated with protection of cells from injury elevation of GSH or induction of either HO-1 or HSP-70 blocks injury/apoptosis in response to TNF-alpha, NO, or H2O2. These are likely critical mechanisms for vascular homeostasis and may be involved in protection/survival in inflammation, ischemia/reprefusion, or in cancer where oxidants, cytokines and NO potently affect vascular cells. The mechanisms by which NO GSH levels or elevates regulates expression of these proteins are not clear. In each case either NO or a variety of oxidants have been found to activate mechanisms leading to the response seen. In this regard, NO-mediated signaling is analogous to oxidant signaling and the pathways involved are likely to be similar. In fact, in addition to activation of ras, NO has been found to activate stress activated pathways leading to increased activity of MAP kinase p38 and c-jun NH2-terminal kinases (JNKs) and, activation of these pathways has been shown to be involved in adaptive/protective mechanisms initiated by NO. Since both oxidants and NO appear to activate similar stress responses and appear to activate similar stress activated mechanisms, we propose to test the hypothesis that NO induces adaptive responses in vascular cells through redox activation/regulation of MAP kinase signaling pathways and modifies responses to other agents through similar mechanisms. In this project we will determine the role of MAP kinases in adaptive responses (GSH synthesis, stress protein induction) using vascular smooth muscle and endothelial cells.
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