The cellular and molecular responses of the lung to oxidative stress involve increased expression of antioxidant enzymes and stress-response genes, including the stress-inducible gene heme oxygenase-1 (HO-1). Heme oxygenase (HO) catalyzes the first and rate-limiting step in the degradation of heme to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratory and others have established that HO-1 provides potent cytoprotection against oxidant-induced lung injury including but not limited to hyperoxia, LPS, and ischemia/reperfusion. Accumlating data from our own laboratory and others strongly suggest that the cytoprotective effects of HO-1 are mediated by the catalytic by-products of HO-1, namely ferritin, bilirubin and CO. In particular, we have accumulated data that CO may mediate HO-1 induced cytoprotection by conferring potent anti-inflammatory, anti-apoptotic, and anti-proliferative effects. Furthermore, we have delineated several important signaling pathways by which HO-1 or CO mediate its' cytoprotection. Since the discovery of HO-1 in 1968, the scientific community up to now has accepted the dogma that HO-1 is primarily localized in the rough endoplasmic reticulum. We believe that our most recent observations (see Preliminary Studies) that HO-1 is also localized in the caveolae in pulmonary endothelial cells present a new paradigm and opens up new avenues of research in this field. Thus, for the competitive renewal of this grant, based on our published work (Progress Report) and Preliminary Studies, we have chosen to propose studies to test the following novel hypothesis: Hypothesis: Sub cellular localization of HO-1 in the caveolae plays an important role in contributing to the cytoprotection of HO-1 against oxidative stress. Furthermore, caveolin-1 in caveolae helps regulate the activity and function of HO-1, and the signaling pathways by which HO-1 or CO mediates cytoprotection against oxidative stress. We will test the hypothesis by addressing the following aims: a) To determine the regulation and function of the sub-cellular localization of HO-1 in caveolae of pulmonary endothelial cells; b) To determine the regulation and function of the sub-cellular localization of biliverdin reductase in caveolae of pulmonary endothelial cells; and c) To determine the mechanism by which caveolin-1 regulates HO-1 cytoprotective functions.
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