Effects And Mechanisms Of Intermedin On Cardiac Function And Sympathetic Neural Remodeling In A Rat Model Of Post Myocardial Infarction Heart Failure

Objective:Heart failure(HF)is a clinical syndrome which characterized by the continuous interaction between the underlying myocardial dysfunction and the compensatory neurohumoral mechanisms.Ventricle remodeling and activation of the sympathetic nervous system after myocardial infarction contribute to cardiac dysfunction and development of HF.Increased cardiac sympathetic nerve activity may also lead to the development of cardiac sympathetic hyperinnervation,also known as sympathetic neural remodeling,which is more obvious in the peri-infarct zone.Sympathetic neural remodeling after myocardial infarction is associated with oxidative stress.Intermedin(IMD)is a novel member of the calcitonin gene-related peptide(CGRP)family and has a wide range of regulatory and protective effects on the cardiovascular system.IMD reportedly protects against myocardial ischemia/reperfusion injury via inhibition of oxidative stress.However,whether IMD can improve cardiac function and prevent sympathetic neural remodeling after myocardial infarction via inhibition of oxidative stress remains unclear.This experiment is to elucidate the effects and mechanisms of long-term administration of IMD on the cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction HF.Methods:The HF model was induced in Sprague Dawley(SD)rats by ligation of the left anterior descending coronary artery.Male SD rats were randomly divided into 3 groups: Sham group,HF group,HF+IMD group.Rats in the sham group underwent sham operation without LAD coronary artery ligation,and were administrated subcutaneously with saline by a mini-osmotic pump for 4 weeks.Rats in the HF and HF+IMD group were administrated subcutaneously with saline or IMD by a mini-osmotic pump for 4 weeks after surgery.At the end of the study,cardiac function was assessed by echocardiography and cardiac catheterization.Left ventricular ejection fraction(LVEF)and fractional shortening(LVFS)were calculated;systolic blood pressure(SBP),diastolic blood pressure(DBP),left ventricular end-diastolic pressure(LVEDP)and the maximal rate of left ventricular pressure increase and decrease(±LVdp/dtmax)were recorded.Ventricular fibrillation threshold(VFT)measurement was performed to access the incidence of ventricular arrhythmia.Then the rats were killed and blood samples were collected to detect the B-type natriuretic peptide(BNP)level.The heart was excised and rinsed in cold saline and the left ventricle was weighed after atria and right ventricle were trimmed off.Left ventricle weight/body weight(LVW/BW)was calculated and the peri-infarct zone was obtained.The densities of tyrosine hydroxylase(TH)and growth associated protein 43(GAP43)immunoreactive nerve fibers were determined by immunohistochemistry study.The protein expressions of nerve growth factor(NGF),TH and GAP43 in ventricular myocardium were studied by western blot.The activity of superoxide dismutase(SOD)and the level of malondialdehyd(MDA)in peri-infarct zone were also examined.Results:In comparison to the HF group,IMD treatment significantly increased the LVEF and LVFS(P<0.05).The SBP,DBP were decreased in the HF+IMD group compared with sham group and HF group(P<0.05)。The LVEDP in the HF+IMD group was lower than that in the HF group,while the ±LVdp/dtmax were increased in the HF+IMD group compared to HF group(P<0.05).The plasma BNP level was reduced in the HF+IMD group than that of HF group(P<0.05).IMD treatment also decreased the LVW/BW value in the HF+IMD group compared with the HF group(P<0.05).Compared with the HF group,IMD treatment significantly increased the VFT(P<0.05).A significant decrease in the densities of TH-and GAP43-positive nerve fibers was observed in the HF+IMD group in comparison to the HF group(P<0.05).The protein expressions of TH,GAP43 and NGF were significantly lower in the HF+IMD group than that in the HF group(P<0.05).Moreover,compared to the HF group,the SOD activity in the peri-infarct zone of HF+IMD group was significantly increased,while the MDA level was significantly decreased(P<0.05).Conclusion:Long-term administration of IMD can improve cardiac function of a failing heart,reduce the plasma BNP level and attenuate ventricle remodeling.IMD also can suppress sympathetic neural remodeling after myocardial infarction and reduce the incidence of ventricle arrhythmia,which may be associated with its anti-oxidative property.