Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Ultrasound, Children's Hospital of Nanjing Medical University, Nanjing, China.
Life Sci. 2018 Aug 1;206:106-116. doi: 10.1016/j.lfs.2018.04.010. Epub 2018 Apr 18.
Sepsis-induced myocardial dysfunction represents a major cause of death. Alamandine is an important biologically active peptide. The present study evaluated whether alamandine improves cardiac dysfunction, inflammation, and apoptosis, and affects the signaling pathways involved in these events. Experiments were carried out in mice treated with lipopolysaccharide (LPS) or alamandine, and in neonatal rat cardiomyocytes. Alamandine increased the ejection fraction and fractional shortening, both of which were decreased upon LPS infusion in mice. LPS and alamandine reduced blood pressure, and increased the expression of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in the heart in mice. The LPS-induced decrease in α-myosin heavy chain (MHC) and β-MHC, and increase in S100 calcium binding protein A8 (S100A8) and S100A9, were reversed by alamandine pre-treatment. Alamandine pre-treatment prevented LPS-induced myocardial inflammation, apoptosis and autophagy. LPS increased p-ERK, p-JNK, and p-p38 levels, which were inhibited by alamandine. Dibutyryl cyclic AMP (db-cAMP) increased p-ERK, p-JNK, and p-p38 levels, and reversed the inhibitory effects of alamandine on the LPS-induced increase in p-ERK, p-JNK, and p-p38. Moreover, db-cAMP reduced the expression of α-MHC and β-MHC in cardiomyocytes, and reversed the almandine-induced attenuation of the LPS-induced decrease in α-MHC and β-MHC. These results indicate that alamandine attenuates LPS-induced cardiac dysfunction, resulting in increased cardiac contractility, and reduced inflammation, autophagy, and apoptosis. Furthermore, alamandine attenuates sepsis induced by LPS via inhibiting the mitogen-activated protein kinases (MAPKs) signaling pathways.
脓毒症诱导的心肌功能障碍是主要的死亡原因。阿马林是一种重要的生物活性肽。本研究评估了阿马林是否能改善心功能障碍、炎症和细胞凋亡，并影响涉及这些事件的信号通路。实验在给予脂多糖（LPS）或阿马林的小鼠和新生大鼠心肌细胞中进行。阿马林增加了射血分数和缩短分数，而 LPS 输注则降低了这两项指标。LPS 和阿马林降低了小鼠的血压，并增加了心脏中诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（eNOS）的表达。LPS 诱导的α-肌球蛋白重链（MHC）和β-MHC 减少，以及 S100 钙结合蛋白 A8（S100A8）和 S100A9 的增加，被阿马林预处理所逆转。阿马林预处理可预防 LPS 诱导的心肌炎症、细胞凋亡和自噬。LPS 增加了 p-ERK、p-JNK 和 p-p38 的水平，而这些水平被阿马林抑制。二丁酰环 AMP（db-cAMP）增加了 p-ERK、p-JNK 和 p-p38 的水平，并逆转了阿马林对 LPS 诱导的 p-ERK、p-JNK 和 p-p38 增加的抑制作用。此外，db-cAMP 降低了心肌细胞中α-MHC 和β-MHC 的表达，并逆转了阿马林对 LPS 诱导的α-MHC 和β-MHC 减少的抑制作用。这些结果表明，阿马林减轻了 LPS 诱导的心肌功能障碍，导致心肌收缩力增加，炎症、自噬和细胞凋亡减少。此外，阿马林通过抑制丝裂原活化蛋白激酶（MAPKs）信号通路来减轻 LPS 诱导的脓毒症。
