Abstract：
OBJECTIVE: Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure. Thus, there is an urgent need for more effective strategies to aid in cardiac protection. Our previous work found that sphingosine-1-phosphate (S1P) could ameliorate cardiac hypertrophy. In this study, we aimed to investigate whether S1P could prevent cardiac fibrosis and the associated mechanisms in cardiac remodeling.
METHODS: Eight-week-old male C57BL/6 mice were randomly divided into a sham, transverse aortic constriction (TAC) or a TAC+S1P treatment group.
RESULTS: We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease in α-smooth muscle actin (α-SMA) and collagen type I (COL I) expression compared with the TAC group. We also found that one of the key S1P enzymes, sphingosine kinase 2 (SphK2), which was mainly distributed in cytoblasts, was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro. In addition, our in vitro results showed that S1P treatment activated extracellular regulated protein kinases (ERK) phosphorylation mainly through the S1P receptor 2 (S1PR2) and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine.
CONCLUSIONS: These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart. This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling.
METHODS: Eight-week-old male C57BL/6 mice were randomly divided into a sham, transverse aortic constriction (TAC) or a TAC+S1P treatment group.
RESULTS: We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease in α-smooth muscle actin (α-SMA) and collagen type I (COL I) expression compared with the TAC group. We also found that one of the key S1P enzymes, sphingosine kinase 2 (SphK2), which was mainly distributed in cytoblasts, was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro. In addition, our in vitro results showed that S1P treatment activated extracellular regulated protein kinases (ERK) phosphorylation mainly through the S1P receptor 2 (S1PR2) and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine.
CONCLUSIONS: These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart. This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling.
摘要：
目的：心脏重构是各种心血管疾病的常见病理改变，最终可导致心力衰竭。因此，迫切需要更有效的策略来辅助心脏保护.我们以前的工作发现，鞘氨醇-1-磷酸（S1P）可以改善心脏肥大。在这项研究中,我们旨在研究S1P是否可以预防心脏纤维化以及心脏重塑的相关机制.
方法：将8周龄雄性C57BL/6小鼠随机分为假手术组，横主动脉缩窄(TAC)或TAC+S1P治疗组。
结果：我们发现S1P治疗可改善TAC小鼠的心功能，TAC+S1P组的心肌纤维化比率明显低于TAC组，并伴有α-平滑肌肌动蛋白(α-SMA)和I型胶原(COLI)表达的降低。我们还发现一种关键的S1P酶，鞘氨醇激酶2（SphK2），主要分布在成纤维细胞中，在心脏重塑病例中下调，在体内和体外S1P治疗后恢复。此外,我们的体外研究结果表明,S1P处理主要通过S1P受体2(S1PR2)激活细胞外调节蛋白激酶(ERK)的磷酸化,并促使p-ERK在暴露于去氧肾上腺素的H9c2细胞中从细胞质转座成细胞.
结论：这些发现提示SphK2和S1PR2/ERK通路可能参与了S1P对心脏的抗重塑作用。因此，这项工作揭示了一种预防心脏重塑的新型潜在疗法。
方法：将8周龄雄性C57BL/6小鼠随机分为假手术组，横主动脉缩窄(TAC)或TAC+S1P治疗组。
结果：我们发现S1P治疗可改善TAC小鼠的心功能，TAC+S1P组的心肌纤维化比率明显低于TAC组，并伴有α-平滑肌肌动蛋白(α-SMA)和I型胶原(COLI)表达的降低。我们还发现一种关键的S1P酶，鞘氨醇激酶2（SphK2），主要分布在成纤维细胞中，在心脏重塑病例中下调，在体内和体外S1P治疗后恢复。此外,我们的体外研究结果表明,S1P处理主要通过S1P受体2(S1PR2)激活细胞外调节蛋白激酶(ERK)的磷酸化,并促使p-ERK在暴露于去氧肾上腺素的H9c2细胞中从细胞质转座成细胞.
结论：这些发现提示SphK2和S1PR2/ERK通路可能参与了S1P对心脏的抗重塑作用。因此，这项工作揭示了一种预防心脏重塑的新型潜在疗法。
