Abstract
Helix B surface peptide (HBSP) is an erythropoietin (EPO)-derived peptide that protects tissue from the risks of elevated blood pressure and thrombosis. This study focused on the protection of HBSP in hepatic ischaemia/reperfusion (I/R) by enhancing the level of autophagy. In detail, we randomly divided C57BL/6 mice into sham-operated, hepatic ischaemia/reperfusion (I/R), I/R + HBSP, I/R + HBSP + 3-methyladenine (autophagy inhibitor), I/R + HBSP + rapamycin (mTOR inhibitor), and I/R + HBSP + Ly294002 (Akt inhibitor) groups. We assessed alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in mouse sera, and performed haematoxylin/eosin (HE) staining, immunohistochemistry, electron microscopy, immunofluorescence microscopy, and western blotting on liver tissue to detect the degree of liver injury, liver apoptosis, autophagy, and the expression of microtubule associated protein 1 light chain 3 alpha (Map1lc3, or LC3), Beclin 1, phospho-mTOR, mTOR, phospho-Akt (P-Akt), and Akt. HBSP relieved hepatic I/R injury in a concentration-independent manner. The expression of LC3II, LC3I, and Beclin 1, and the formation of autophagosomes, in the I/R + HBSP group were higher than those in the I/R group. The protective effects of HBSP were abolished by 3-methyladenine and, to a lesser extent, Ly294002, but enhanced by rapamycin. Furthermore, In vivo, HBSP also protected against hypoxia injury induced by cobalt chloride (CoCl2) through improving the level of autophagy. Therefore, HBSP protected against hepatic I/R injury, mainly via regulating autophagy by targeting mTOR.
Highlights
A large number of literatures have confirmed that Erythropoietin (EPO) has tissue protection and erythropoiesis
Inhibition of mTOR phosphorylation with rapamycin[27,28] reinforced autophagy (Fig. 4B), alleviated the infiltrated inflammatory cells (Fig. 4C), and intensified the ALT and AST levels (Fig. 4D) compared with the levels in the Helix B surface peptide (HBSP) group. These findings suggest that the protective effects of HBSP on the liver are bolstered by enhancing autophagy via inhibition of phospho-mTOR
Studies showed that autophagy played an important role in different I/R injury[30,31,32,33] and increased autophagy was believed to have a beneficial effect on liver I/R injury[34,35,36]
Summary
A large number of literatures have confirmed that Erythropoietin (EPO) has tissue protection and erythropoiesis. As HBSP does not interact with Epor[24], unlike EPO, it does not promote the production of red blood cell[5] It is not associated with the side effects of thrombosis and hypertension. Since autophagy was first recognized due to its role during starvation, the study of autophagy in liver disease has focused on hepatic I/R injury[13], during which it renders cells more effective in response to nutritional deficits and hypoxia. A large number of studies have confirmed the protective role of autophagy in the kidney, lower limbs, myocardium, nerve tissue of multiple organs, and tissue affected by I/R injury[20,21,22,23], but its role in the liver is still not clear[24]. We uncovered the mechanism of HBSP protecting hepatic I/R injury
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