Corticosterone-Induced Myocardial Dysfunctions and the Cardioprotective Role of Tauroursodeoxycholic Acid: An Experimental Study in Mice

Background

Major depressive disorder increases cardiovascular risk through stress-induced elevated cortisol levels. Tauroursodeoxycholic acid (TUDCA), a bile acid, has been reported to have anti-inflammatory, anti-depressive and cardioprotective effects. However, the effects of stress-induced myocardial dysfunctions remain unclear. Our study aims to investigate corticosterone-induced myocardial dysfunctions and the role of TUDCA in rescuing such dysfunctions.

Methods

To achieve this, experiments were conducted on mice that had been exposed to corticosterone, with treatment involving TUDCA. We first evaluated depression-like behaviours using the open field test, forced swimming test and sucrose preference test, and assessed cardiac function using echocardiography. We then analysed the levels of norepinephrine (NE), adenosine triphosphate (ATP) and B-cell lymphoma-2 (Bcl-2)/Bcl-2 Associated X-protein (Bax) using liquid chromatography-mass spectrometry, enzyme-linked immunosorbent assay and Western blot, respectively. Finally, we investigated gene expression and signalling pathways through RNA-sequencing, which were further validated by qRT-PCR.

Results

The results demonstrate that corticosterone administration induced depression-like behaviours in mice, including a significant increase in immobility time during the tail suspension test and a significant decrease in the sucrose preference rate. Additionally, it induced cardiac dysfunction in mice, including a decrease in ejection fraction and fractional shortening. Furthermore, corticosterone administration resulted in an increase in left ventricular volume-systolic and left ventricular end-systolic volume index in the mouse left ventricular myocardium. Moreover, it elevated the NE concentration in mouse serum and decreased ATP levels and the Bcl-2/Bax protein expression ratio in the mouse left ventricular tissue. Notably, these detrimental changes were rescued by TUDCA treatment. Additionally, corticosterone affected genes related to cardiac muscle contraction and mitochondrial function, while TUDCA countered this impact by modulating genes associated with muscle processes and ion transport, potentially alleviating myocardial contractile dysfunction.

Conclusion

Overall, our results suggest that corticosterone induces depression-like behaviours, cardiac dysfunction, elevated serum NE levels, reduced ATP and a decreased Bcl-2/Bax ratio, disrupting myocardial contraction and mitochondrial function. TUDCA effectively reversed these effects and modulated genes linked to muscle contraction and ion transport, highlighting its potential in mitigating corticosterone-induced behavioural and cardiac impairments.