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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070274-04
Application #
6879119
Study Section
Pathology A Study Section (PTHA)
Program Officer
Buxton, Denis B
Project Start
2002-05-16
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$432,500
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sawada, Naoki; Liao, James K (2014) Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis. Antioxid Redox Signal 20:1251-67
Tanaka, Shin-ichi; Fukumoto, Yoshihiro; Nochioka, Kotaro et al. (2013) Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 33:1591-600
Montalvo, J; Spencer, C; Hackathorn, A et al. (2013) ROCK1 & 2 perform overlapping and unique roles in angiogenesis and angiosarcoma tumor progression. Curr Mol Med 13:205-19
Hung, Ming-Jui; Cherng, Wen-Jin; Hung, Ming-Yow et al. (2012) Increased leukocyte Rho-associated coiled-coil containing protein kinase activity predicts the presence and severity of coronary vasospastic angina. Atherosclerosis 221:521-6
Wang, Chao-Yung; Liao, James K (2012) A mouse model of diet-induced obesity and insulin resistance. Methods Mol Biol 821:421-33
Zhou, Qian; Mei, Yu; Shoji, Takuhito et al. (2012) Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis. Circulation 126:2236-47
Wang, Qing Mei; Stalker, Timothy J; Gong, Yulan et al. (2012) Inhibition of Rho-kinase attenuates endothelial-leukocyte interaction during ischemia-reperfusion injury. Vasc Med 17:379-85
Liao, James K (2012) Mitohormesis: another pleiotropic effect of statins? Eur Heart J 33:1299-301
Zhou, Qian; Gensch, Christoph; Liao, James K (2011) Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease. Trends Pharmacol Sci 32:167-73
Hata, Takaki; Goto, Chikara; Soga, Junko et al. (2011) Measurement of Rho-associated kinase (ROCK) activity in humans: validity of leukocyte p-MBS/t-MBS in comparison with vascular response to fasudil. Atherosclerosis 214:117-21

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