Activation of STIM1/Orai1‑mediated SOCE in sepsis‑induced myocardial depression

Abstract

Unbalanced Ca2+ homeostasis serves an essential role in the occurrence and development of septic myocardial injury. However, the mechanism of Ca2+ homeostasis in septic myocardial depression is poorly understood due to the complexity of Ca2+ transporters in excitable cells. It was therefore hypothesized that cardiac dysfunction, myocardial injury and cardiac apoptosis in septic myocardial depression are associated with elevated intracellular Ca2+ concentrations caused by stromal interaction molecule 1 (STIM1)/Orai calcium release‑activated calcium modulator 1 (Orai1)‑mediated store‑operated Ca2+ entry (SOCE). A septic myocardial depression model was established using the cecal ligation and puncture operation (CLP) in mice and was simulated in H9C2 cells via lipopolysaccharide (LPS) stimulation. Cardiac function, myocardial injury, cardiac apoptosis and the expression levels of Bax, Bcl‑2, STIM1 and Orai1 were quantified invivo at6, 12and24h. Changes in the intracellular Ca2+ concentration, SOCE and the distribution of STIM1 were assessed invitro within 6h. The morphological changes of heart tissue were observed by hematoxylin‑eosin staining. Myocardial cellular apoptosis was determined by TUNEL method. The expression of Bax, Bcl‑2, STIM1 and Orai1 were visualized by western blot. Cytosolic calcium concentration and SOCE were evaluated by confocal microscopy. The results demonstrated that cardiac contractile function was significantly reduced at6h and morphological changes in cardiac tissues, as well as the myocardial apoptosis rate, were markedly increased at6, 12and24h following CLP. mRNA and protein expression levels of Bax/Bcl‑2 were significantly enhanced at6and12h and glycosylation of Orai1 in the myocardium of septic mice was significantly increased at6h following CLP. The intracellular Ca2+ concentration, SOCE, was significantly increased at1‑2h and the clustering and distribution of STIM1 were markedly changed in H9C2 cells at1and2h. These findings suggested that myocardial dysfunction, cardiac injury and myocardial depression may be related to increased intracellular Ca2+ concentration resulting from STIM1/Orai1‑mediated SOCE, which may provide a potential method to alleviate septic myocardial depression.