Neuregulin-1 Protects Cardiac Function Through Multiple Targets In Sepsis

Objective: Sepsis is an organ dysfunction that threatens a patient’s life caused by the host’s unbalanced response to infection,with a mortality rate of up to 20%.Sepsis is accompanied by many serious complications and various organ dysfunctions.Myocardial injury and cardiac insufficiency are one of them.Myocardial injury is also the key cause of patient death.Studying the target of cardiac insufficiency due to myocardial injury in sepsis is of great significance for exploring potential treatment methods.The mechanism of myocardial insufficiency caused by sepsis is very complicated.The damage of myocardial vascular endothelial cells,excessive oxidative stress,and the accumulation of inflammatory factors and other factors lead to myocardial ischemia and injury,which is important for the development of myocardial injury in sepsis mechanism.NRG-1 plays a vital role in regulating the adaptability of the heart to physiological and pathological stress.NRG-1 / Er Bbs can reduce the apoptosis of cardiomyocytes caused by hypoxia,reduce mitochondrial dysfunction,and reduce inflammation.Therefore,the purpose of this study is to explore the role of NRG-1 in improving sepsis myocardial injury through multiple targets,and to provide a theoretical basis for the treatment of sepsis and cardiac insufficiency.Methods: Thirty-six SPF-free male SD rats(N = 36,8-10 weeks old,weight300-400g)were divided into Sham group(n = 12)and LPS group(n = 12).And NRG-1 group(n = 12);each group consists of two subgroups(the treatment time is 24 hours and 48 hours respectively),a total of 6 groups,namely Sham 24 h group(n = 6),LPS 24 h group(n = 6),NRG-1 24 h group(n = 6)and Sham 48 h group(n = 6),LPS48 h group(n = 6),and NRG-1 48 h group(n = 6).Rats in the LPS group and NRG-1group were induced to establish a sepsis model by intraperitoneal injection of 10 mg /kg of LPS.Rats in the Sham group were injected with the same amount of saline at the same time and at the same site.In the NRG-1 24 h group and the NRG-1 48 h group,rh NRG-1 was injected into the tail vein at two time points,5h,5h,and 24 h after surgery;other rats were injected with the same amount of saline at the same time and at the same site.Rats in the 24 h and 48 h groups were harvested at 24 and 48 hours after surgery,respectively.The mental state and activity of the rats were closely observed at any time within 4 hours after surgery,and the survival was recorded every 6 hours.At the end of cardiac function measurement,blood samples were collected from rat inferior vena cava,and after centrifugation,the levels of ICAM-1,VEGF,and inflammatory factors(TNF-α and IL-6)in rat serum were measured by ELISA;Nitrate reductase method was used to detect the serum NO level;Western blot was used to detect the expression of Rho A and ROCK1 signal channel proteins in rat left ventricle tissue;HE staining was used to observe the pathological changes of myocardial tissue;transmission electron microscope was used to observe the ultrastructure of myocardial cells and mitochondria Changes;TUNEL method was used to detect myocardial cell apoptosis;immunofluorescence method was used to detect myocardial vascular endothelial cell marker v WF level.After taking tissue and blood samples from each group of rats,they were euthanized with carbon dioxide,and their spinous processes were displaced to confirm death.In addition,cultured rat H9c2 cells further verified the effect of NRG-1 on the expression of Rho A and ROCK1 signal channel proteins in vitro.Results The 48-hour survival rate of rats in the LPS group was 50%,and the48-hour survival rate of the NRG-1 group increased to 83.3%.The cardiac function status of the rats in the NRG-1 group was significantly enhanced.The specific manifestations were that the MAP,LVSP,and ±dp/dt max in the NRG-1 group were higher than those in the LPS group,while LVEDP was decreased.Compared with the LPS group,the myocardial fibers of the NRG-1 group were arranged in an orderly manner,the inflammatory cell aggregation was reduced,the myocardial cells and mitochondria were less swollen,the v WF expression in myocardial vessels increased,and apoptotic myocardial cells were reduced.It is suggested that NRG-1 may improve the barrier function of myocardial vascular endothelial cells.In the NRG-1 group,the levels of serum inflammatory factors TNF-α and IL-6,endothelial-related factors ICAM-1,VEGF and NO were significantly reduced,and the number of apoptotic cardiomyocytes was reduced.It is suggested that NRG-1 may participate in the processes related to endothelial cell protection,inflammation and apoptosis.In addition,compared with the LPS group,the expressions of Rho A and ROCK1 signal channel proteins in myocardial tissue and H9c2 cardiomyocytes cultured in vitro were reduced in the NRG-1 group,suggesting that the Rho A/ROCK1 signaling pathway may be involved in the occurrence of sepsis and the heart The process of protecting endothelial cells during functional impairment.Conclusion NRG-1 exerts effects through multiple targets,including protecting the structure and function of myocardial vascular endothelial cells,enhancing myocardial vascular barrier function,improving cardiac hemodynamics,exerting anti-inflammatory,anti-apoptotic,and anti-oxidative stress effects,thereby Improve the degree of myocardial injury and increase survival rate.Therefore,NRG-1 may be a potential treatment for cardiac insufficiency in sepsis.