Corticosteroids are potent anti-inflammatory agents, which are used in the treatment of asthma, hypersensitivity reactions, and autoimmune diseases. Corticosteroids inhibit the inflammatory response through binding to the glucocorticoid receptor (GR). The GR is a steroid hormone nuclear receptor which when bound to corticosteroids, modulates the expression of target genes by binding to DNA sequences containing glucocorticoid response element (GRE). Although most studies have focused on the GRE-mediated effects of corticosteroids, there is considerable controversy regarding the nuclear actions of OR, particularly in mediating some of the more rapid anti-inflammatory effects of corticosteroids. In cardiovascular disease, corticosteroids exert both beneficial and detrimental effects. Corticosteroids protect the myocardium from ischemic injury, presumably through an anti-inflammatory mechanism. However, corticosteroid therapy can also lead to cardiac rupture, which has precluded their use in acute myocardial infarction. This detrimental effect of corticosteroids has been attributed to its GRE-mediated inhibitory effects on wound healing and cardiac remodeling. Therefore, defining the potential role of non-nuclear OR in cardiovascular diseases could have important therapeutic implications; especially in the development of selective OR modulators which can distinguish between the nuclear and non-nuclear effects of OR.

In our pilot studies, we have found that activation of endothelial nitric oxide synthase (eNOS) by corticosteroids is mediated via the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt pathway. Based upon these results, we propose to determine how GR activates P13K; whether GR interacts directly with P13K in a ligand-dependent manner; whether this occurs by non-transcriptional or non-GRE-mediated mechanism; and whether this interaction can be generalized to other members of the steroid hormone family of nuclear receptors. Once the interaction site(s) on OR is pinpointed, the physiological significance of this pathway will be tested in mutated OR "knock-in" mice. The significance of these proposed studies is that by linking the OR to P13K, a potential critical step in the non-nuclear action of corticosteroids is suggested and the role of OR is considerably broadened since PI3KIAkt and NO are known to mediate diverse cellular functions.

R01HL070274

2002-05-16

2008-03-31