Corticosteroids Inhibit Cell Death Induced by Doxorubicin in Cardiomyocytes: Induction of Antiapoptosis, Antioxidant, and Detoxification Genes

Abstract

Psychological or physical stress induces an elevation of corticosteroids in the circulating system. We report here that corticosterone (CT) protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox), an antineoplastic drug known to induce cardiomyopathy possibly through reactive oxygen species production. The cytoprotection induced by CT is within the range of physiologically relevant doses. The lowest dose tested, 0.1 M (or 3.5 g/dl), inhibited apoptosis by approximately 25% as determined by caspase activity. With 1 M CT, cardiomyocytes gain a cytoprotective effect after 8 h of incubation and remain protected for at least 72 h. Hydrocortisone, cortisone, dexamethasone, and aldosterone but not androstenedione or cholesterol also induced cytoprotection. Analyses of 20,000 gene expression sequences using Affymetrix high-density oligonucleotide array found that CT caused up-regulation of 140 genes and down-regulation of 108 genes over 1.5-fold. Among the up-regulated genes are bcl-xL, metallothioneins, glutathione peroxidase-3, and glutathione Stransferases. Western blot analyses revealed that CT induced an elevation of bcl-xL but not bcl-2 or proapoptotic factors bax, bak, and bad. Inhibiting the expression of bcl-xL reduced the cytoprotective effect of CT. Our data suggest that CT induces a cytoprotective effect on cardiomyocytes in association with reprogramming gene expression and induction of bcl-xL gene.

Insulin-like growth factor-1 restores dexamethasone-induced heart growth arrest in rats: the role of the ubiquitin pathway

“…Indeed, glucocorticoids have been demonstrated to have anti-apoptotic effects in heart muscle tissue as well as in cultured cardiomyocytes. [38][39][40] Altogether, the above findings suggest that the heart is relatively resistant to the catabolic actions of DEXA compared to skeletal muscle.…”

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

“…Similar attenuation of apoptosis by glucocorticoids has been shown in neonatal rat cardiomyocytes. 33 In contrast, Scheuer and Mifflin 20 reported detrimental effects using pharmacological doses of glucocorticoids and no effect when lower levels were used. Several studies have used the potent synthetic glucocorticoid dexamethasone in experimental ischemia-reperfusion 34 and clinically as dexamethasoneeluting stents to reduce intimal hyperplasia, with mixed reports for both beneficial outcomes 34 -36 and higher restenosis rates in patients with diabetes mellitus.…”

Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

“…The first study (Inchiosa Jr and Smith, 1990) only evaluated survival, whereas the effect of glucocorticoids on DOX toxicity was only evaluated in vitro (Chen et al, 2005). At present, our study quantifies to what extent cardioprotection occurred in animals cotreated with DEX, KP and monoHER.…”

“…In vitro data showed that DOX affected both the viability and neutrophil adhesion of endothelial cells with clinically achievable concentrations (Abou El Hassan et al, 2003). These inflammatory effects may play a role in DOX-induced cardiotoxicity and results of some studies support these indications (Inchiosa Jr and Smith, 1990;Chen et al, 2005;Hou et al, 2005).…”

“…It has indeed been suggested that inflammation is another source of CML formation (Daugherty et al, 1994;Anderson and Heinecke, 2003). It has, however, to be noticed that glucocorticoids and NSAIDs also have antioxidant properties (Hamburger and Mc Cay, 1990;Kataoka et al, 1997;Ozmen, 2005;Chen et al, 2005;Yamada et al, 2006) besides their antiinflammatory properties (Koehler et al, 1990;Masferrer and Seibert, 1994;Auphan et al, 1995;Scheinman et al, 1995;Morteau, 2000). As a representative of the NSAIDs, we used KP because it is a strong non-selective COX-inhibitor and it is available for s.c. injection.…”