Abstract
AimSigma-1 receptors have been investigated and shown to play a protective role in both depression and cardiovascular disease. SA4503, known as a σ1 receptor agonist, regulates cardiac calcium and potassium channels in rat models of depression. However, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to chronic mild stress.Methods and ResultsSprague-Dawley male rats received 28-day treatment with SA4503, simultaneously with chronic mild stress. Behavior measurements were assessed after the daily doses. Additionally, a multielectrode array assessment, electrophysiological study, immunohistochemistry analysis, histological analysis, and Western blot analysis were performed. Depression rats’ hearts showed abnormal electrical activity, including disordered excitation propagation and prolonged total activation time (TAT). In addition, atrial arrhythmias (AAs), induced by burst stimulation, showed higher incidence and longer duration in the depression group compared to the control group. These changes were related to reduced conduction junctions and enhanced spatial heterogeneity. Importantly, depressed rat hearts showed greater expression of inflammatory factors (TGF-α, IL-6, and TGF-β), more collagen distribution in the extracellular matrix, and lower expression of gap junction proteins (CX40 and CX43). Furthermore, SA4503 partially mitigated the above indices in the depression group (P < 0.01 for all groups).ConclusionThese findings show the effects of the σ1R agonist SA4503; it alleviates atrial myocardial inflammation and conduction junctions after chronic mild stress. SA4503 may be the promising pharmacological agent to treat depression-related AAs by increasing conduction function, improving the expression of connexin 40 and 43, and reducing cardiac myocardial inflammation.
Highlights
The sigma-1 receptor (σ receptor, Sigma-1 receptor (S1R)) is a molecular chaperon protein that is widely expressed in numerous tissues, including the brain and heart, and localizes on the endoplasmic reticulum (ER), which borders the mitochondria (Hayashi and Su, 2007)
The sucrose preference results showed significantly reduced sucrose preference in the major depression disorder (MDD) rats, with MDS rats exhibiting a significant increase in sucrose preference compared with the MDD rats after the fourth week of chronic unpredictable mild stress (CUMS) (Figure 1C)
We report that connexin 40 (Cx40) and connexin 43 (Cx43) expression levels are significantly reduced in depression model rats, which could be reversed by SA4503
Summary
The sigma-1 receptor (σ receptor, S1R) is a molecular chaperon protein that is widely expressed in numerous tissues, including the brain and heart, and localizes on the endoplasmic reticulum (ER), which borders the mitochondria (Hayashi and Su, 2007). Our previous study found that S1R activation produced antiarrhythmic effects with reversed expression of voltage-dependent L-type calcium channels and potassium channels in a rat model of depression. Recent studies have established that inflammation might create an environment for the progress of AF. Inflammatory factors such as TNF-α participated in the initiation and perpetuation of AF while AF could accelerate immune responses, causing an “AF begets AF” phenomenon. TNF-α, secreted mainly by activated macrophages, plays a vital role in atrial fibrosis and redistributes the expression of connexin 40 (Cx40) and connexin 43 (Cx43), contributing to local conduction disturbances (Sawaya et al, 2007). Despite existing findings regarding AAs after depression, it remains unknown whether SA4503 can alleviate myocardial inflammation or conduction junctions in the atrium after exposure to depression
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