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

Yasuharu Shinoda,Kohji Fukunaga,Hideyuki Hasegawa,Hideaki Tagashira,Md Shenuarin Bhuiyan,Hiroshi Kanai,Chen Zhang,Feng Han

doi:10.1371/journal.pone.0163992

Yasuharu Shinoda, Kohji Fukunaga + Show 6 more

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https://doi.org/10.1371/journal.pone.0163992

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Abstract

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 heart failure induced by TAC were associated with depression-like behaviors concomitant with downregulation of σ1R expression in brain 6 weeks after surgery. σ1R levels significantly decreased in astrocytes in both the hippocampal CA1 region and dentate gyrus. Oral administration of the specific σ1R agonist SA4503 (0.3–1.0mg/kg) significantly improved TAC-induced depression-like behaviors concomitant with rescued astrocytic σ1R 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 σ1R expression in hippocampus. Furthermore, the glucocorticoid receptor antagonist mifepristone antagonized depressive-like behaviors and ameliorated decreased hippocampal σ1R expression in TAC mice. We conclude that elevated corticosterone levels trigger hippocampal σ1R downregulation and that σ1R stimulation with SA4503 is an attractive therapy to improve not only cardiac dysfunction but depression-like behaviors associated with heart failure.

Highlights

The prevalence of depression in heart failure (HF) patients has drawn attention because it is associated with poorer clinical outcomes [1, 2]
Since selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine and sertraline are potent σ1 receptor (σ1R) ligands, we recently focused on cardioprotective mechanisms of SSRI through the σ1R in heart failure models using transverse aortic constriction (TAC) mice and ovariectomised rats [5,6,7]
Since σ1R stimulation with the novel σ1R agonist SA4503 reportedly improves depressionlike behaviors in olfactory bulbectomized rats [22], we tested potential anti-depression effects of SA4503 in TAC mice

Summary

Introduction

The prevalence of depression in heart failure (HF) patients has drawn attention because it is associated with poorer clinical outcomes [1, 2]. Administration of selective serotonin reuptake inhibitors (SSRIs) to MI patients reduces post-MI morbidity and mortality [3]. It remains unclear whether MI causes depression, because the relationship of the heart to emotional responses is largely unknown. Since selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine and sertraline are potent σ1R ligands, we recently focused on cardioprotective mechanisms of SSRI through the σ1R in heart failure models using transverse aortic constriction (TAC) mice and ovariectomised rats [5,6,7]. Σ1R is highly expressed in neonatal rat cardiomyocytes and in brain [8, 9]. σ1R protein levels in left ventricle markedly decreased accompanied by progression of left ventricular hypertrophy in TAC mice and σ1R protein expression was significantly and positively correlated with impaired LV fractional shortening [7]

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