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. 2014 Sep 29;9(9):e106827.
doi: 10.1371/journal.pone.0106827. eCollection 2014.

Glucocorticoid modulates angiotensin II receptor expression patterns and protects the heart from ischemia and reperfusion injury

Qin Xue  1 , Andrew J Patterson  1 , Daliao Xiao  1 , Lubo Zhang  1
Affiliations

Glucocorticoid modulates angiotensin II receptor expression patterns and protects the heart from ischemia and reperfusion injury

Qin Xue et al. PLoS One. .

Abstract

Glucocorticoid regulates angiotensin II receptor (ATR) expression via activating glucocorticoid receptors and binding to glucocorticoid response elements. The regulation of ATR by glucocorticoids in the context of myocardial injury from ischemia/reperfusion (I/R) is yet to be elucidated. The present study determined the role of ATR in glucocorticoid-induced cardiac protection. Adult male rats were administered once a day i.p. 1 mg/kg/day dexamethasone or dexamethasone plus 10 mg/kg/day RU486 for 5 days. Hearts were then isolated and subjected to I/R injury in a Langendorff preparation. Dexamethasone treatment significantly decreased I/R injury and improved post-ischemic recovery of cardiac function. Dexamethasone increased glucocorticoid receptor binding to glucocorticoid response elements at AT1aR and AT2R promoters, resulting in a significant increase in expression of AT1R protein but a decrease in AT2R expression in the heart. In addition, dexamethasone treatment significantly increased PKCε expression and p-PKCε protein abundance. These dexamethasone-mediated effects were blocked by RU486. More importantly, blockade of AT1R and AT2R with losartan and PD123319 abrogated dexamethasone-induced protection of the heart from I/R injury. The results indicate that glucocorticoid promotes a cardioprotective phenotype associated with the upregulation of AT1R and PKCε and downregulation of AT2R in the heart.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Effects of dexamethasone on AT1R and AT2R mRNA and protein.
Hearts were isolated from animals treated with vehicle control, dexamethasone (DEX), DEX + RU486 (RU). AT1R and AT2R protein (A) and mRNA (B) abundance was determined by Western blots and real time RT-PCR, respectively. Data are means ± SEM. Data were analyzed by one-way ANOVA. * P<0.05, DEX vs. control or DEX+RU486, n = 4.
Figure 2
Figure 2. Effects of dexamethasone on cardiac ischemia and reperfusion injury.
Hearts were isolated from animals treated with vehicle control, dexamethasone (DEX), DEX + RU486 (RU), and were subjected to 20 minutes of ischemia and 30 minutes of reperfusion injury in a Langendorff preparation. Losartan (L, 1 µM) and PD123319 (PD, 0.3 µM) were added 5 minutes before ischemia and continuously present in the perfusion buffer during ischemia/reperfusion period. Post-ischemic recovery of left ventricular function and infarct size were determined. LDH release over 30 minutes of reperfusion was measured as area under curve (AUC). Data are means ± SEM. Data were analyzed by two-way ANOVA. * P<0.05, DEX vs. control or DEX+RU486, n = 6.
Figure 3
Figure 3. Effects of individual application of losartan and PD123319 on dexamethasone-induced cardiac protective effect.
Hearts were isolated from animals treated with vehicle control or dexamethasone (DEX) and were subjected to 20 minutes of ischemia and 30 minutes of reperfusion injury in a Langendorff preparation. Losartan (L, 1 µM) or PD123319 (PD, 0.3 µM) were added 5 minutes before ischemia and continuously present in the perfusion buffer during ischemia/reperfusion period. Post-ischemic recovery of left ventricular function and infarct size were determined. Data are means ± SEM. Data were analyzed by two-way ANOVA. * P<0.05, DEX vs. control or DEX+L, n = 4-9.
Figure 4
Figure 4. Effects of dexamethasone on GR protein abundance.
Hearts were isolated from animals treated with vehicle control, dexamethasone (DEX), DEX + RU486 (RU). Total and nuclear GR protein abundance was determined by Western blots. Data are means ± SEM. Data were analyzed by one-way ANOVA. * P<0.05, DEX vs. control or DEX+RU486, n = 4.
Figure 5
Figure 5. Effects of dexamethasone on GR binding affinity to GREs at the AT1aR and AT2R promoters.
Hearts were isolated from animals treated with vehicle control, dexamethasone (DEX), DEX + RU486 (RU). Competition EMSA was performed with pooled nuclear extracts (n = 5) with the increasing ratio of unlabeled/labeled oligonucleotides encompassing the GRE2 at the AT1aR promoter (A) or the GRE4 at the AT2R promoter (B). Data are means ± SEM. The slopes were analyzed by one-way ANOVA. * P<0.05, DEX vs. control or DEX+RU486.
Figure 6
Figure 6. Effects of dexamethasone on GR binding to GREs at the AT1aR and AT2R promoters.
Hearts were isolated from animals treated with vehicle control, dexamethasone (DEX), DEX + RU486. Binding of the GR to GREs at the AT1aR (A) and AT2R (B) promoters was determined by ChIP assays using a GR antibody. Data are means ± SEM. Data were analyzed by one-way ANOVA. * P<0.05, DEX vs. control or DEX+RU486, n = 5.
Figure 7
Figure 7. Effects of dexamethasone on PKCε and PKCδ expression.
Hearts were isolated from animals treated with vehicle control, dexamethasone (DEX), DEX + RU486 (RU). PKCε, PKCδ, p-PKCε, and p-PKCδ protein abundance (A) and PKCε and PKCδ mRNA abundance (B) were determined by Western blots and real time RT-PCR, respectively. Data are means ± SEM. Data were analyzed by one-way ANOVA. * P<0.05, DEX vs. control or DEX+RU486, n = 4.
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