Protective effect of mild hypothermia on sepsis-induced myocardial injury by mediating the GRP78/PERK/ATF4 axis
HU Weiwei
ZHANG Ting
ZHANG Xiaohong
Abstract：Objective To observe the protective effect of mild hypothermia on myocardial injury in septic rats and the underlying mechanism related with endoplasmic reticulum(ER)stress.Methods A total of 32 male SD rats were randomly divided into the control group,mild hypothermia group,sepsis group,sepsis+mild hypothermia group,with 8 rats in each group.The sepsis model was established by intraperitoneal injection of lipopolysaccharide(LPS 10mg/kg).A hypothermia therapy device was used for whole-body physical cooling,and anal temperature was monitored.Changes in rat cardiac function were recorded with the cardiac function analysis system.Enzyme-linked immunosorbent assay was performed to measure serum tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6),cardiac troponin I(cTnI)and creatine kinase MB(CK-MB).Pathological methods were applied to observe changes in the rat myocardium.Protein levels of GRP78,p-PERK and ATF4 were detected by Western blot.Another 32 male SD rats were subjected to oral gavage of GSK2606414 for 2 weeks.Grouping and experiments were similarly conducted.Results Compared with the control group,rats in the sepsis group had reduced cardiac function,more severe pathological damages to the myocardium and mitochondria,higher serum TNF-α,IL-6,cTnI and CK-MB,and higher protein expressions of ER markers GRP78,p-PERK and ATF4 in the myocardium(P＜0.05).Compared with the sepsis group,rats in the sepsis+mild hypothermia group showed alleviated pathological damages to the myocardium and mitochondria,lower left ventricular end-diastolic pressure(LVEDP),serum TNF-α,IL-6,cTnI and CK-MB,and protein expressions of ER markers GRP78,p-PERK and ATF4 in the myocardium,but higher left ventricular diastolic pressure,+dP/dtmax,and-dP/dtmax(P＜0.05).After administration of PERK inhibitors,serum TNF-α,IL-6,cTnI,and CK-MB levels were reduced and similar between the sepsis group and sepsis+mild hypothermia group.PERK inhibitors alleviated sepsis-induced myocardial damage.They also reduced protein levels of GRP78,p-PERK and ATF4,and comparable between the sepsis group and sepsis+mild hypothermia group.Conclusion Mild hypothermia can exert a better protective effect on myocardial injury in septic rats by inhibiting the GRP78/PERK/ATF4 axis and alleviating ER stress.
Keywords：mild hypothermiasepsismyocardial injuryendoplasmic reticulum stressGRP78/PERK/ATF4
Publication Date：2025-11-26
Online Publishing Date：2025-12-12(First online date of this platform, not the publication date of the document)
Pages：5( 1792-1796 )