Search

The aim of the current study was to investigate the effect and mechanism of schisandrin B (Sch B) on myocardial hypertrophy induced by pressure overload in mice. Male C57BL/6J mice were randomly divided into three groups: i) Sham (n=12); ii) transverse aortic constriction (TAC) (n=12); and iii) Sch B-treated (n=12; 80 mg·kg-1·d-1 per gavage). The model of myocardial hypertrophy was established by constricting the descending branch of the aortic arch. Following a 4-week treatment period, cardiac remodeling was evaluated using echocardiography and pathological and molecular analysis. Sch B improved cardiac function in the Sch B-treated group compared with the TAC group. Moreover, the Sch B-treated group had a smaller myocardial cell cross-sectional area and less fibrosis compared with the TAC group. The protein expression levels of cardiac hypertrophy and fibrosis markers in the TAC group were significantly higher compared with those in the sham group. The same markers in the Sch B-treated group were significantly lower compared with those in the TAC group. Additionally, the phosphorylation levels of the mitogen-activated protein kinase (MAPK) signaling pathway-associated proteins extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2 and P38 mitogen-activated protein kinase were significantly lower in the Sch B-treated group compared with the TAC group. Further in vitro investigation demonstrated that Sch B prevented the adverse effects of angiotensin II-induced hypertrophy and fibrosis by inhibiting the MAPK signaling pathway in H9c2 cells. In conclusion, Sch B may improve pathological myocardial remodeling and cardiac function induced by pressure overload, and its underlying mechanism may be associated with inhibition of the MAPK signaling pathway.

Endoplasmic reticulum stress (ERS)-induced apoptosis serves a crucial role in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). Previous studies have confirmed that pleckstrin homology-like domain family A member 3 (PHLDA3) is an important mediator in ERS-associated apoptosis. The aim of the current study focused on whether PHLDA3 served protective effects on hypoxia/reoxygenation (H/R)-injured cardiomyocytes by inhibiting ERS-induced apoptosis. Furthermore, the molecular mechanisms associated with the PI3K/AKT signaling pathway were investigated. Primary neonatal rat cardiomyocytes were isolated and randomized into four groups: i) Control + adenovirus encoding scrambled short hairpin RNA (AdshRNA); ii) control + adenoviral vectors encoding PHLDA3 shRNA (AdshPHLDA3); iii) H/R+ AdshRNA and iv) H/R+AdshPHLDA3. AdshPHLDA3 was used to knock down PHLDA3. An H/R injury model was constructed by treatment with hypoxia for 4 h followed by reoxygenation for 6 h. A PI3K/AKT inhibitor, LY294002, was supplemented in mechanistic studies. Cell viability and LDH/CK releases were detected to evaluate myocardial damage. Flow cytometry assays were used to assess apoptotic response. Western blotting assays were used to detect protein expression. The results demonstrated that H/R induced myocardial damage and increased PHLDA3 expression. ERS-induced apoptosis was significantly increased following H/R injury, as indicated by increased apoptotic rates and ERS-associated protein expression, including those of CHOP, 78 kDa glucose-regulated protein and caspase-12. However, PHLDA3 inhibition following AdshPHLDA3 transfection reversed cell damage and ERS-associated apoptosis on H/R injury. Studies for molecular mechanisms concluded that the apoptosis-inhibition effects and cardioprotective roles of PHLDA3 inhibition were induced partly by the activation of the PI3K/AKT pathway, which was verified by LY294002 treatment. In conclusion, in the process of H/R injury, PHLDA3 inhibition reduced ERS-induced apoptosis and H/R injury by activating the PI3K/AKT pathway. PHLDA3 may be a therapeutic target for the treatment of MIRI.