Stress is known to cause an increase in the synthesis of corticosteroids by the adrenal glands. Although corticosteroids have been shown to contribute to the pathophysiology of suppressed Immune response and a number of psychiatric disorders, the effect of CT on the heart remains unclear. Doxorubicin (Dox) is an anti-neoplastic drug that can produce chronic cardiac toxicity which is manifested as dilated cardiomyopathy. An important feature of this form of cardiomyopathy is the apoptosis of cardiomyocytes. Our preliminary studies found that corticosterone (CT) pretreatment prevented Dox from inducing apoptosis of cardiomyocytes. The glucocorticoid receptor antagonist mifepristone prevented CT from inducing a cell survival response. Several forms of g!ucocorticoids, aldosterone, progesterone and retinoic acid but not estrogen, testosterone or L-thyroxin can inhibit apoptosis of cardiomyocytes. Analyses of ERK, Akt and SGK-1 activities or bcl-2 expression indicated that CT neither activated the known survival kinases nor elevated the expression of the anti-apoptotic gene bcl- 2. The conditioned medium of CT-treated cardiomyocytes shows partially cytoprotective effective. The TranSignal array approach found that CT treatment could potentially activate 21 transcription factors. We hypothesize that activation of the glucocorticoid receptor initiates transcriptional activation of survival genes in cardiomyocytes in vitro and in vivo.
Specific aims of this grant include: 1) To test if CT binding causes its receptor to interact with and to activate multiple transcription factors in cardiomyocytes; 2) To test that the activation of cell survival genes contributes to CT-induced cytoprotection; and 3) To demonstrate that CT protects the heart from cardiomyopathy induced by Dox in vivo via inducing the transcription of cell survival genes. This project will combine our expertise in genomics, transcriptomics and proteomics to systematically study the linkage between the glucocorticoid receptor and cell survival mechanisms. Given the fact that stress is unavoidable in our daily life, this project will provide novel information to advance our understanding in the biological effect of corticosteroids on the heart. More importantly, since apoptosis has been shown to contribute to heart failure induced by the chemotherapy agent Dox as well as by many forms of cardiovascular disease, our finding and proposed mechanistic study will provide a hope for novel therapy against heart failure in the future. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076530-04
Application #
7214886
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Schwartz, Lisa
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$357,938
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Morrissy, Steve J; Sun, Haipeng; Zhang, Jack et al. (2016) Differential Regulation of Bcl-xL Gene Expression by Corticosterone, Progesterone, and Retinoic Acid. J Biochem Mol Toxicol 30:309-16
Aguilar, David; Strom, Joshua; Chen, Qin M (2014) Glucocorticoid induced leucine zipper inhibits apoptosis of cardiomyocytes by doxorubicin. Toxicol Appl Pharmacol 276:55-62
Xu, Beibei; Zhang, Jack; Strom, Joshua et al. (2014) Myocardial ischemic reperfusion induces de novo Nrf2 protein translation. Biochim Biophys Acta 1842:1638-47
Aguilar, David C; Strom, Josh; Xu, Beibei et al. (2013) Expression of glucocorticoid-induced leucine zipper (GILZ) in cardiomyocytes. Cardiovasc Toxicol 13:91-9
Zhang, J; Chen, Q M (2013) Far upstream element binding protein 1: a commander of transcription, translation and beyond. Oncogene 32:2907-16
Zhang, Jack; Dinh, Thai Nho; Kappeler, Kyle et al. (2012) La autoantigen mediates oxidant induced de novo Nrf2 protein translation. Mol Cell Proteomics 11:M111.015032
Morrissy, Stephen; Strom, Joshua; Purdom-Dickinson, Sally et al. (2012) NAD(P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes. Cardiovasc Toxicol 12:108-14
Kappeler, Kyle V; Zhang, Jack; Dinh, Thai Nho et al. (2012) Histone deacetylase 6 associates with ribosomes and regulates de novo protein translation during arsenite stress. Toxicol Sci 127:246-55
Xu, Beibei; Strom, Joshua; Chen, Qin M (2011) Dexamethasone induces transcriptional activation of Bcl-xL gene and inhibits cardiac injury by myocardial ischemia. Eur J Pharmacol 668:194-200
Terrand, Jerome; Xu, Beibei; Morrissy, Steve et al. (2011) p21(WAF1/Cip1/Sdi1) knockout mice respond to doxorubicin with reduced cardiotoxicity. Toxicol Appl Pharmacol 257:102-10

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