Protective Effects Of Neuregulin-1β On Chronic Contractibility Cardiac Failure And Correlative Mechanisms Research

Background and objectivesWith the advent of the 21st century, heart failure has emerged as a major component of the massive public health problem of cardiovascular disease. Despite the substantial clinical advances, heart failure still has become a major cause of human cardiovascular morbidity and mortality worldwide.It thus remains a challenge to develop novel drugs with new mechanisms of action for the treatment of heart failure.The ErbB family of receptor tyrosine kinases and their ligands, neuregulins are critical involved not only in cardiac development but also in the maintenance of structural and functional integrity of the adult heart. Neuregulin-1s are widely expressed signaling molecules that are involved in cell differentiation, proliferation, growth, survival, and apoptosis. They transmit their signals by interacting with cell membrane receptors of the ErbB family, resulting in the activation of intracellular signaling cascades, which participate in various physiological and etiological processes. It has been reported that if reduced ErbB expression leads to reciprocal increases in sympathetic tone in the failing heart, this may promote progressive myocardial dysfunction. As a correlate, increased levels of Nrg-1 improve and decreased levels exacerbate progression of heart failure in animals. These observations have led to the possibility that recombinant Nrg-1 has therapeutic potential in patients with heart disease, an exciting possibility currently under investigation.Our research is divided into two parts to observe the protective effects of Neuregulin-1βon Chronic contractibility cardiac failure and to explore the correlated mechanisms. We hope that via our efforts some useful messages can be provided for this relative new therapeutic target in heart failure.Methods1. Tail vein injection with cardiac toxicity of anticancer drug doxorubicin hydrochloride, record of animal survival and weight changes and detection:①indicators of cardiac function;②hemodynamics;③the pathological changes and cardiomyocyte apoptosis;④serum indicators of oxidative stress.2. Tail vein injection of doxorubicin hydrochloride at the same time the tail vein of exogenous Neuregulin-1βintervention for 10 days, a separate experiment that the positive control group ADM + Cedilanid, negative control group ADM + excipients, model group, normal control group.Detection:①-④the same as part1;⑤the concentration of BNP in plasma and cTNT in serum;⑥RT-PCR and real-time fluorescence quantitative PCR were used to detection the expression of MHC-αand MHC-βmRNA in myocardial cells.3. Randomly clinical selection of patients with chronic systolic heart failure were treated with Neuregulin-1β+ chronic heart failure standard treatment; placebo group and negative control group were also set up. Observed:1) the main effect indicators:①cardiac systolic function and the exercise tolerance;②Nt-proBNP concentration; 2) secondary effects indicators:①Cardiothoracic ratio;②NYHA classification of cardiac function;③the quality of life improvements;④dyspnea assessment;3) security indicators:①the changes of vital signs and changes in 12-lead ECG;②conventional laboratory testing indicators;③side effects and adverse events. 4) the level of sFas concentration.Results1. Weight gain of adriamycin-induced rats was significantly slow;the chamber of heart was expanded obviously(p<0.01)and the systolic function was decreased obviously(p<0.01) LVEDPwere significantly increased(p<0.01) and LVSP,±dp/dtmax were significantly decreased(p<0.01). The rate of cardiomyocyte apoptosis was increased obviously (p<0.01); the pathological change of cardiac muscle was serious.CHF was the main cause for death.The concentration of SOD was decreased significantly(p<0.01)but the concentration of NOS,MDA increased significantly(p<0.01) in model rats.2. The survival rate of ADM+Nrg-1βgroup was increased and the heart chamber was significantly decreased(p<0.01) and the systolic function was increased obviously(p<0.01). LVEDPwere significantly decreased(p<0.05) and LVSP,±dp/dtmax were significantly increased(p<0.05).The rate of cardiomyocyte apoptosis in ADM+Nrg-1βgroup was much lower and the pathological change of cardiac muscle was less damage. The level of cTNT in serum and BNP in plasma were significantly decreased (p<0.05)in ADM+Nrg-1βgroup and the level of SOD in serum were significantly increased (p<0.05)on the contrary the level of MDA,NOS in serum were significantly decreased(p<0.05).3. The mRNA copies of MHC-αin ADM+Nrg-1βgroup was increased on the contrary the mRNA copies of MHC-βwas decreased.4. Compared with the other control groups, Cardiac systolic function of the patients in Nrg-1βgroup was significantly improved mainly for the reduction of LVESV and the increase of LVEF. In this group, distance of 6MWT increased significantly and the level of Nt-proBNP in plasma was significant decreased after the 1 month follow-up period.In Nrg-1βgroup,there are different degrees of improvement in cardiothoracic ratio,cardiac function,quality of life score and dyspnea assessment comparing to the control groups.There was no significant change in vital signs before and after administration. There was no obvious outlier in the main indicators of laboratory tests. The main side effects was gastrointestinal reaction and showed no serious adverse reactions.5. In Nrg-1βgroup the level of sFas in serum was significant decreased comparing with the control groups.Conclusion1. Low-dose intravenous injection and a long cycle of cardiac toxicity drugs - doxorubicin hydrochloride, can be ideal to establish animal model with chronic systolic heart failure, the pathological changes are the same as dilated cardiomyopathy in clinical medicine. The results suggest that adriamycin-induced cardiac toxicity of the drug-mediated oxidative stress involved in the occurrence and development of heart failure.2. Given exogenous Neuregulin-1βcan significantly improve the Adriamycin-induced cardiac contractile function in heart failure, reducing the extent of myocardial injury, regulate the level of oxidative stress and significantly reduce cardiomyocyte apoptosis; its mechanisms may be related to regulating the transformation of the cardiac myosin heavy chainαsubunit andβsubunit.3. Recombinant Human Neuregulin-1βtreatment of chronic non-ischemic heart failure can improve cardiac systolic function, improve the patient's exercise tolerance, and there is no significant change in vital signs before and after administration. There is no obvious outlier in the main indicators of laboratory tests. The main side effects of gastrointestinal reaction showed no serious adverse reactions. It can reduce the level of serum sFas which induce the inhibition of myocyte apoptosis. This may be one of the correlative mechanisms of Neuregulin-1βin the treatment of chronic systolic heart failure.