Alamandine attenuates sepsis-associated cardiac dysfunction via inhibiting MAPKs signaling pathways
Alamandine attenuates sepsis-associated cardiac dysfunction via inhibiting MAPKs signaling pathways
复制标题
Alamandine 通过抑制 MAPK 信号通路减轻脓毒症相关的心脏功能障碍
DOI：
10.1016/j.lfs.2018.04.010
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发表时间：
2018-08-01
期刊：
影响因子：
6.1
通讯作者：
Kong, Xiang-Qing
中科院分区：
文献类型：
--
作者：
Li, Peng;Chen, Xi-Ru;Kong, Xiang-Qing
脓毒症引起的心肌功能障碍是死亡的主要原因。阿拉曼丁是一种重要的生物活性肽。本研究评估了Alamandine是否改善心功能不全、炎症和细胞凋亡，并影响参与这些事件的信号通路。实验在用脂多糖（LPS）或alamandine处理的小鼠和新生大鼠心肌细胞中进行。Alamandine增加小鼠的射血分数和缩短分数，这两者在LPS输注后均降低。LPS和Alamandine均能降低小鼠血压，增加心脏诱导型一氧化氮合酶（iNOS）和内皮型一氧化氮合酶（eNOS）的表达。alamandine预处理可逆转LPS诱导的α-肌球蛋白重链（MHC）和β-MHC的降低以及S100钙结合蛋白A8（S100 A8）和S100 A9的增加。Alamandine预处理可预防LPS诱导的心肌炎症、细胞凋亡和自噬。LPS使p-ERK、p-JNK和p-p38水平升高，而alamandine可抑制p-ERK、p-JNK和p-p38水平升高。二丁酰环腺苷酸（db-cAMP）增加p-ERK，p-JNK，和p-p38水平，并逆转alamandine对LPS诱导的p-ERK，p-JNK，和p-p38增加的抑制作用。此外，db-cAMP降低心肌细胞中的α-MHC和β-MHC的表达，并逆转almandine诱导的LPS诱导的α-MHC和β-MHC的减少的减弱。这些结果表明，阿拉曼丁减弱LPS诱导的心脏功能障碍，导致心脏收缩力增加，并减少炎症，自噬和细胞凋亡。此外，alamandine通过抑制丝裂原活化蛋白激酶（MAPK）信号通路减轻LPS诱导的脓毒症。
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 alpha-myosin heavy chain (MHC) and beta-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 alpha-MHC and beta-MHC in cardiomyocytes, and reversed the almandine-induced attenuation of the LPS-induced decrease in alpha-MHC and beta-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.