Stress and vitamin D: Altered vitamin D metabolism in both the hippocampus and myocardium of chronic unpredictable mild stress exposed rats

Summary

Exposure to stressful life events is associated with the onset of major depression and increases the risk of cardiac morbidity and mortality. While recent evidence has indicated the existence of an interrelationship between local vitamin D (VD) metabolism and many aspects of human physiology including brain and heart function, much is still unknown concerning the biological link between VD signaling and stress-induced depressive behavior and cardiac dysfunction. In the present study, we observed the VD intracrine system in the hippocampus and myocardium of chronic unpredictable mild stress (CUMS) exposed rats. After 4 weeks of CUMS procedure, rats were induced to a depressive-like state and the cytochromes P450 enzymes involved in VD activating and catabolizing (CYP27B1 and CYP24A1 respectively) and VD receptor (VDR) were assessed by real time RT-PCR and western blot in the hippocampus, myocardium and kidney. In the hippocampus of depressed rats, CYP27B1, CYP24A1 and VDR expression were significantly increased and the local status of 1,25-dihydroxyvitamin D (1,25(OH)₂D) was higher compared with controls. Furthermore, hippocampal mRNA levels of VD target genes (calbindin-d28k, neurotrophin-3) and RXR_α (heterodimeric partner of VDR) were upregulated in response to chronic stress. Similar to the hippocampus, CUMS also induced CYP27B1/CYP24A1/VDR expression in the myocardium. However, renal metabolism of VD and serum1,25(OH)₂D status were unchanged. Meanwhile, sertraline treatment could partly normalize the stress-induced alterations of VD metabolism. In conclusion, this study firstly showed a co-elevated expression of CYP27B1/CYP24A1/VDR in both the hippocampus and myocardium of CUMS rats, which suggests VD signaling may be involved in the compensatory mechanism that protect from stress-induced deteriorating effects on the brain and heart.

Introduction

The precipitation of a depressive episode has been linked to stressful life events, which increases the risk of cardiac morbidity and mortality (Pereira et al., 2012). Depression now is recognized as an independent risk factor for cardiovascular (CV) disease. Individuals with major depression have a risk of myocardial infarction (MI) four times higher than the norm (Pratt et al., 1996). Psychosocial factors and depression account for 32.5% of the attributable risk for an MI (Rosengren et al., 2004). CUMS is accepted as a valid animal model of depression. Chronic stress not only leads to depressive behavior but also causes abnormal cardiac function in rats, such as elevated heart rate, reduced heart rate variability, elevated sympathetic tone, and exaggerated reactivity to stressors (Lavie et al., 2011). The association between stress, depression and CV disease is intricate and the molecular mechanisms underpinning the relationship between heart and brain are elusive.

VD has been recently suggested as a pleiotropic secosteroid concerning many aspects of human physiology. Sub-optimal VD status is being associated with a number of psychiatric conditions and CV problems (Barnard and Colon-Emeric, 2010). Although the classical role of VD in bone formation and calcium–phosphate homeostasis has been well established, a full understanding of its nonskeletal functions is still on the way. The hormonal precursor VD is either ingested in the diet or derived from 7-dehydrocholesterol in the skin upon ultraviolet light exposure. In hepatic cells, VD is hydroxylated into its major circulating metabolite, 25-hydroxyvitamin D (25(OH)D). It then undergoes activation and elimination through 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) respectively (Adams and Hewison, 2010). Circulating 25(OH)D provides substrates for CYP27B1 to convert to the active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D), which serves as a high affinity ligand for the vitamin D receptor (VDR) in target tissues. After ligand binding, VDR forms a heterodimer with retinoid X receptor (RXR) and acts on VD-response elements (VDREs), exerting transcriptional control over a batch of genes (Kato et al., 2007).

Although circulating 1,25(OH)₂D is primarily synthesized and catabolized in the kidney, the extra-renal expression of CYP27B1 and CYP24A1 is thought to be important for local production of 1,25(OH)₂D. Over the past several years, the cytochromes P450 enzymes involved in VD metabolism and VD receptor (VDR) have been mapped not only in intestines and kidney to maintain calcium-phosphate homeostasis, but also in pancreas, heart, brain, adipose tissues and endocrine or immune system, suggesting the paracrine or intracrine properties of VD (Bouillon et al., 2008). VD action in a particular cell depends upon the metabolic synthesis or delivery of sufficient concentrations of 1,25(OH)₂D ligand and expression of adequate VDR and RXR coreceptor proteins. Therefore, the maintenance of adequate 25(OH)D status is necessary for optimal intracrine actions of 1,25(OH)₂D and VD deficiency is associated with higher risk for mental illness and cardiac dysfunction (Bell, 2011).

Depressive patients always have low VD status and are at a risk of bone loss. According to a recently published meta-analysis, tendency to depression in persons with low serum concentration of VD seems to be higher compared to those with sufficient VD status (Anglin et al., 2013). However, it is still debatable whether VD insufficiency is the cause of depression or just secondary to depressive syndrome, due to inadequate VD intake and less ultraviolet exposure (Rastmanesh et al., 2012).

Hippocampus is one of the most vulnerable brain regions to various stressors and hippocampal atrophy caused by stress-elevated adrenal glucocorticoid hormones has been repeatedly documented as a principal contributor to depression (Banasr et al., 2011). The stress-induced increase of cortisol secretion also worsen CV prognosis in depressed patients (Nair et al., 2012). VD is a neural and cardiac protective agent against glucocorticoid excess with intracrine actions (Obradovic et al., 2006, Ahmed, 2012). Since observational studies also strongly associate VD deficiency with a variety of CV disease, it has been hypothesized that VD may play a role in the coexistence of depression and excess CV events caused by chronic stress (May et al., 2010).

The relationship between VD local metabolism and the stress-induced psychosomatic disorders is interesting and blank. Thus, the main objective of the present study was to evaluate the effect of CUMS on the VD metabolism in hippocampus, myocardium and kidney and the influence of chronic treatment of the selective serotonin reuptake inhibitor (SSRI), sertraline, was also studied.