Modulation of the JNK/c-Jun/HSP27 pathway in cardiomyocytes under chronic stress-induced cardiac dysfunction: Therapeutic implications of Tauroursodeoxycholic acid.

Abstract

AIMS: Depression significantly increases the risk of cardiovascular diseases (CVD) by exacerbating hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and oxidative stress damage, common risk factors for both conditions. Our study aims to elucidate how elevated corticosterone levels in mice induced by chronic unpredictable mild stress (CUMS), an experimental model showing depression-like behaviors, contribute to the cardiac oxidative damage and dysfunction, and to assess the protective role of tauroursodeoxycholic acid (TUDCA) in this process. RESULTS: CUMS mice show electrocardiogram abnormalities, decreased cardiomyocyte size, increased perivascular fibrosis, and elevated circulating corticosterone. CUMS mice exhibit heightened oxidative stress in the left ventricular myocardium, evidenced by increased ROS levels and decreased SOD, GSH levels, and fewer mitochondria with evidence of damage. This oxidative imbalance is accompanied by a reduced BCL2/BAX protein ratio and a higher percentage of TUNELcardiomyocytes, confirming myocardial apoptosis. TUDCA treatment reverses these effects, restoring redox balance and cardiomyocyte survival. RNA-Seq reveals downregulated Jun and Hspb1 genes involved in oxidative stress, while JNK/c-Jun activation and HSP27 suppression in CUMS mice, TUDCA treatment reverses these proteins change. In vitro, TUDCA reverses the reduced AC-16 cell viability and mitochondrial function, increases ROS levels, and decreases SOD and GSH levels induced by cortisol. Treatment with c-Jun inhibitor T-5224 and JNK agonist Anisomycin confirms cortisol's activation of JNK/c-Jun signaling, inhibition of HSP27 expression, and reduction of SOD and GSH levels, all of which are counteracted by TUDCA. CONCLUSION: Elevated corticosterone levels in depression contribute to cardiac dysfunction through oxidative damage. TUDCA mitigates these effects via the JNK/c-Jun/HSP27 pathway, which offers potential therapeutic implications for depression-associated cardiac dysfunction.