Abstract TP17: Activation Of Erk1/2 Signaling Drives Cardiac Hypertrophy During Chronic Mild Stress-induced Depression In Mice

Abstract

Background: Major depressive disorder (MDD) is one of the fastest-growing disability disorders in the US and worldwide. Extensive clinical data suggest that MDD is associated with an increased risk of hypertension, coronary heart disease, and other cardiovascular diseases. A close relation between cardiovascular and cerebrovascular diseases and clinical evidence presents a potential link between depression and stroke. MDD when combined with other comorbidities, makes the prognosis worse. Dysregulation of the sympathetic nervous system, impaired hypothalamic-pituitary-adrenal axis, and increased inflammatory response are plausible mechanisms that have been linked to depression-induced cardio- and cerebrovascular complications. In the current study, we investigated cardiac structural and functional alterations in a mouse model of chronic mild stress (CMS) exhibiting depression-like behavior. Methods and Results: The mice were divided into control (CT) and CMS groups. The CMS mice were subjected to various mild, unpredictable stressors for 7 weeks. Depression-like traits were confirmed in the CMS group by analyses of behavioral changes using open field and forced swim tests and a decrease in hippocampal brain-derived neurotrophic factor (BDNF) protein level. To evaluate depression-associated neuronal damage and neuronal plasticity, Fluoro-Jade C staining and expression of microtubule-associated protein 2 were examined. However, we did not observe neuronal damage in the CMS mice as compared to the CT mice. We also observed a decrease in cardiac BDNF expression and upregulation of IL-6 in the CMS mice compared to the CT group. Echocardiographic and histological analyses showed an increase in ventricular wall thickness with increased cardiomyocyte size in the CMS group. However, we did not find changes in fetal gene expression or fibrosis markers. Investigation of underlying mechanisms showed a significant upregulation in ERK1/2 signaling in the left ventricles of the CMS mice as compared to the control group, with no changes in phospho-p38, NFATc3, or JNK levels. Conclusion: In conclusion, these data suggest that ERK1/2 signaling might have an important role in cardiac hypertrophic response during the CMS-induced depression in mice.