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Corticosteroids Mediate Heart Failure-Induced Depression through Reduced ?1-Receptor Expression.

ABSTRACT: Cardiovascular diseases are risk factors for depression in humans. We recently proposed that ?1 receptor (?1R) stimulation rescued cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) in mice. Importantly, ?1R stimulation reportedly ameliorates depression-like behaviors in rodents. Thus, we hypothesized that impaired ?1R activity in brain triggers depression-like behaviors in animals with cardiovascular disease. Indeed, here we found that cardiac hypertrophy and heart failure induced by TAC were associated with depression-like behaviors concomitant with downregulation of ?1R expression in brain 6 weeks after surgery. ?1R levels significantly decreased in astrocytes in both the hippocampal CA1 region and dentate gyrus. Oral administration of the specific ?1R agonist SA4503 (0.3-1.0mg/kg) significantly improved TAC-induced depression-like behaviors concomitant with rescued astrocytic ?1R expression in CA1 and the dentate gyrus. Plasma corticosterone levels significantly increased 6 weeks after TAC, and chronic treatment of mice with corticosterone for 3 weeks elicited depression-like behaviors concomitant with reduced astrocytic ?1R expression in hippocampus. Furthermore, the glucocorticoid receptor antagonist mifepristone antagonized depressive-like behaviors and ameliorated decreased hippocampal ?1R expression in TAC mice. We conclude that elevated corticosterone levels trigger hippocampal ?1R downregulation and that ?1R stimulation with SA4503 is an attractive therapy to improve not only cardiac dysfunction but depression-like behaviors associated with heart failure.

SUBMITTER: Shinoda Y

PROVIDER: S-EPMC5065174 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression.

Shinoda Yasuharu Y Tagashira Hideaki H Bhuiyan Md Shenuarin MS Hasegawa Hideyuki H Kanai Hiroshi H Zhang Chen C Han Feng F Fukunaga Kohji K

PloS one 20161014 10

Cardiovascular diseases are risk factors for depression in humans. We recently proposed that σ1 receptor (σ1R) stimulation rescued cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) in mice. Importantly, σ1R stimulation reportedly ameliorates depression-like behaviors in rodents. Thus, we hypothesized that impaired σ1R activity in brain triggers depression-like behaviors in animals with cardiovascular disease. Indeed, here we found that cardiac hypertrophy and ...[more]

PMID: 27741227

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Project description:AimsDoxorubicin (DOX)-induced heart failure has a poor prognosis, and effective treatments have not been established. Because DOX shows cumulative cardiotoxicity, we hypothesized that minimal cardiac remodelling occurred at the initial stage in activating cardiac fibroblasts. Our aim was to investigate the initial pathophysiology of DOX-exposed cardiac fibroblasts and propose prophylaxis.Methods and resultsAn animal study was performed using a lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulative dose. Histological analysis was performed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay, picrosirius red staining, and immunohistochemical staining. The mechanism was analysed in vitro with a low dose of DOX, which did not induce cell apoptosis. Microarray analysis was performed. Differentially expressed genes were confirmed by enrichment analysis. Mitochondrial damage was assessed by mitochondrial membrane potential. The production of inflammatory cytokines and fibrosis markers was assessed by western blot, quantitative polymerase chain reaction, and ELISA. A phosphokinase antibody array was performed to detect related signalling pathways. Low-dose DOX did not induced cell death, and fibrosis was localized to the perivascular area in mice. Microarray analysis suggested that DOX induced genes associated with the innate immune system and inflammatory reactions, resulting in cardiac remodelling. DOX induced mitochondrial damage and increased the expression of interleukin-1. DOX also promoted the expression of fibrotic markers, such as alpha smooth muscle actin and galectin-3. These responses were induced through stress-activated protein kinase/c-Jun NH2-terminal kinase signalling. A peroxisome proliferator-activated receptor (PPARγ) agonist attenuated the expression of fibrotic markers through suppressing stress-activated protein kinase/c-Jun NH2-terminal kinase. Furthermore, this molecule also suppressed DOX-induced early fibrotic responses in vivo.ConclusionsLow-dose DOX provoked reactive fibrosis through sterile inflammation evoked by the damaged mitochondria.

Project description:OBJECTIVES:The purpose of this study was to investigate the effects of mineralocorticoid receptor antagonists (MRAs) on systolic blood pressure (SBP) and outcomes according to baseline SBP in patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND:MRAs are greatly underused in patients with HFrEF, often because of fear of adverse events. Concern about hypotension has been raised by the demonstration that MRAs are particularly effective treatment for resistant hypertension. METHODS:The effect of MRA therapy was studied in 4,396 patients with HFrEF randomized in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. RESULTS:Mean SBP change from baseline to 6 months was +1.4 ± 18.1 mm Hg in the placebo group and -1.2 ± 17.9 mm Hg in the MRA group. The between-treatment difference was 2.6 mm Hg (95% confidence interval [CI]: 1.5 to 3.6; p < 0.001). All outcomes were reduced by MRA therapy overall, with consistent effects across SBP categories (e.g., all-cause mortality, overall hazard ratio [HR] of 0.72; 95% CI: 0.64 to 0.82; p < 0.001; SBP ?105 mm Hg; HR: 0.72; 95% CI: 0.56 to 0.94; SBP >105 to ?115 mm Hg; HR: 0.78; 95% CI: 0.60 to 1.02; SBP >115 to ?125 mm Hg; HR: 0.71; 95% CI: 0.53 to 0.94; SBP >125 to ?135 mm Hg; HR: 0.79; 95% CI: 0.57 to 1.10; and SBP > 135 mm Hg; HR: 0.67; 95% CI: 0.50 to 0.90; p for interaction = 0.95). Hypotension was infrequent and not more common with MRA therapy than with placebo, overall (4.6% vs. 3.9%; p = 0.25) or in any SBP category. CONCLUSIONS:MRA treatment had little effect on SBP in patients with HFrEF, and the clinical benefits were not modified by baseline SBP. MRA treatment infrequently caused hypotension, even when the baseline SBP was low. The treatment discontinuation rates between MRA and placebo therapy were similar. Low SBP is not a reason to withhold MRA therapy in patients with HFrEF.

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Corticosteroids Mediate Heart Failure-Induced Depression through Reduced ?1-Receptor Expression.

Publications

Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression.

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