The Study Of The Effect Of NRG-1 On Cardiac Dysfunction In Septic Rats And Its Mechanisms

Sepsis can be defined as "life-threatening organ dysfunction due to a dysregulated host response to infection".With the improvement of critical care treatment technology,the mortality rate of sepsis patients is still as high as 20%.Sepsis can cause myocardial injury and cardiac dysfunction in patients,the complications are also the leading causes of death in patients with sepsis.The mechanisms of sepsis-induced myocardial damage is complicated,which include myocardial ischemia,cardiomyocytes apoptosis,circulatory inhibitors,mitochondrial dysfunction,inhibitory effect of sepsis on myocardium and so on.Neuregulin-1(NRG-1),a member of the epidermal growth factor(EGF)family that plays an important role in the development and maintenance of the nervous system,is a secretory protein found to have multiple biological activities against diseases in cardiovascular system in recent years.NRG-l/ErBb system plays prominent roles of regulating intracellular calcium cycling,suppressing inflammation response and apoptosis.We hypothesize that the various effects derived from NRG-1 are very promising in the treatment of sepsis and can be used as an important means to prevent myocardial injury in sepsis.Male SD rats(8-10 weeks)were divided into sepsis group(CLP,n = 12),sepsis NRG group(CLP-NRG,n = 12),sham group(n = 6)and sham NRG group(n = 6).To get a sepsis model,rats of sepsis group and sepsis NRG group were subjected to cecal ligation and puncture(CLP).Recombinant human nerugulin-1(rhNRG-1)was injected in the tail vein 30min before CLP.The rats of sham NRG group and the sepsis NRG group were injected with rhNRG-1,while the rats of sham group and the sepsis group were injected with the same volume of normal saline 30 minutes before the operation.Four groups of rats were studied 24 hours after surgery,the survival rate of the rats was observed every 4 hours,and the survival rate and survival status of the rats were recorded.24h after the operation,the hemodynamics of rats were measured and the hemodynamics images were recorded.When the hemodynamic test was completed,the left ventricular tissue of rats was taken and the expression of inflammatory factors(TNF-α,IL-1β and IL-6)and calcium regulatory proteins(RyR2,P-RyR2,PLB,P-PLB,SERCA2a)in left ventricular tissues of rats were detected by Western Blot.When the hemodynamic test was completed,the right ventricular tissue of rats was taken and cardiomyocyte apoptosis was detected by TUNEL.The rats in each group were sacrificed after taking the tissue samples.The experimental results show that the 24-hours survival rate of the rats injected with NRG-1 was increased from 50%in the CLP group to 91.7%in the CLP-NRG group,indicating that NRG-1 can significantly increase survival rate of rats in sepsis.24h after the operation,the hemodynamics of rats with sepsis was significantly improved,arterial pressure(MAP),left ventricular systolic pressure(LVSP)and ±dp/dt max were increased,and left ventricular end-diastolic pressure(LVEDP)was decreased in the CLP-NRG group.Compared with the rats of CLP group,the TNF-α,IL-1β,IL-6 and cardiomycyte apoptosis were inhibited in CLP-NRG rats at 24 hours after surgery,which indicate that NRG-1 could be involved in the inhibitory mechanism of myocardial inflammation and cardiomyocyte apoptosis in sepsis.In addition,the activity of calcium regulatory proteins RyR2(P-RyR2,ser2808)and PLB(P-PLB,Ser16/Thr17)and the level of SERCA2a were significantly increased in rats with sepsis compared to rats in the CLP-NRG group and it shows that NRG-1 plays a role in improving the regulation of calcium circulation in patients with sepsis and cardiac dysfunction.In summary,NRG-1 can improve cardiac function,myocardial injury,and survival In septic rats by effectively inhibiting inflammatory responses,cardiom-yocyte apoptosis and calcium circulation dysfunction.Therefore,we believe that NRG-1 may be a potential treatment for cardiac dysfunction and myocardial injury of sepsis.