Alamandine attenuates sepsis-associated cardiac dysfunction via inhibiting MAPKs signaling pathways

• Published in: Life sciences (1973) Vol. 206; pp. 106 - 116
• Main Authors: Li, Peng, Chen, Xi-Ru, Xu, Fei, Liu, Chi, Li, Chang, Liu, Hui, Wang, Hui, Sun, Wei, Sheng, Yan-Hui, Kong, Xiang-Qing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2018; Elsevier BV
• Subjects: Alamandine; Animals; Animals, Newborn; Apoptosis; Apoptosis - drug effects; Attenuation; Autophagy; Autophagy - drug effects; Biological activity; Blood pressure; Blood Pressure - drug effects; Calcium; Calcium-binding protein; Cardiomyocytes; Cyclic AMP; Echocardiography; Extracellular signal-regulated kinase; Heart; Heart Diseases - diagnostic imaging; Heart Diseases - drug therapy; Heart Diseases - etiology; Inflammation; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; MAP Kinase Signaling System - drug effects; Mice; Muscle contraction; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myosin; Neonates; Nitric oxide; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric-oxide synthase; Oligopeptides - antagonists & inhibitors; Oligopeptides - therapeutic use; Phagocytosis; Pretreatment; Proteins; Rats; Sepsis; Sepsis - complications; Signal transduction; Signaling; Stroke Volume - drug effects; Alamandine; Sepsis; Inflammation; Autophagy; Apoptosis
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2018.04.010

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.