The Study Of Effect And Mechanism Of RhEPO On Cardiac Hypertrophy Induced By Pressure-overload

Background: Left ventricular hypertrophy (LVH) is anindependent risk factor for the morbidity and mortality of cardiovascularevents. Pressure-overload is one of main causes for LVH, It has beenreported that oxidative stress and inflammation play an important role forcardiac hypertrophy and progression to cardiac dysfunction induced bypressure-overload.Erythropoietin(EPO) is a multifunction cytokine, Recombinant EPO(rhEPO) administration have been shown to exert non-haematopoieticaleffects including antiapoptotic, antioxidative and anti-inflammatoryeffects to protective cardiac tissue through its interaction with its specificcellular receptor EPOR in animal experiments. So recently it had becamea reaserch focus on treatment for cardiac diseases.Heme oxygenase-1(HO-1) is an inducible enzyme and degrade hemeto bilirubin, carbon monoxide(CO), and iron. Recently numerous studieshave demonstrated that HO-1 as a cytoprotective defense mechanism andits metabolites have effects of antioxidative, anti-inflammatory and anti-apoptotico HO-1 can inhibite cardiomyocyte hypertrophy induced byAng-Ⅱ,ET-1 and pressure-overload. Clinical experiment shown that theincreases in antioxidant defenses joined with increased expression ofHO-1 upon EPO treatment in hemodialysis patients. Based on theses research upon, we plan to investigate the influnceand the effects mechanism of EPO on cardiac hypertrophy induced bypressure-overload in rats without anemia. Meanwhile we investigate therelation of the HO-1 overexpression and the anti-hypertrophic effect ofEPO.Objection: to investigate the effects of EPO on cardiac hypertrophyinduced by pressure,overload in rats. And to exam wheather EPO caninduce HO-1 overexpression in cardiomyocyte. At last, we explorefurther the relation of the HO-1 overexpression and the anti-hypertrophiceffect of EPO.Methods: The rat model of cardiac hypertrophy induced bypressure-overload were established by coarctation of abdominal aorta inWister rats, Rats were randomly allocated to four groups: Sham group,Modle group, rhEPO treatment group, and rhEPO+ZnPP (HO-1inhibitor) group. Rats in rhEPO treatment group were inject rhEPO(1000U/kg) subcutaneously for three times a week after operation. Rats inrhEPO+ZnPP group were injected HO-1 inhibitor ZnPP(lmg/kg) intra-peritoneal before operation, after operation were injected HO-1 inhibitorZnPP(1 mg/kg~*d) intraperitoneally and rhEPO(1000U/kg) subcutaneous-ly. Rats in Sham group were given the same volume of physiologicalsaline. 4 weeks after, Left ventricular mass index (LVMI) was caculated,myocardial pathological change were observed through myocardial routine HE stain, expression of HO-1 in myocardium was observedthrough immunohistochemistry, and the level of SOD, MDA, TNF-αinmyocardium were detected respectively. The data are presented as mean±SD. Comparisons between multiple groups were performed by one-wayANOVA. Comparisons between two groups were performed by LSD-t. Ap value＜0.05 was accepted as statistically significant.Results: Rats in model group developed significant cardiachypertrophy associated with higher LVWI, the myocardium level ofMDA, TNF-αwere higher than in rats in sham group (P＜0.01). The levelof SOD was lower(P＜0.01). Expression level of HO-1 in the myocardiumwas higher (P＜0.01). However, compared with the model group, cardiachypertrophy of rats was significantly relieved in rhEPO treatment group,associated with decreased LVMI, improved SOD, lower the levels ofMDA, TNF-a in myocardium (p＜0.01), And expression level of HO-1 inthe myocardium was higher significantly (P＜0.01). Cotreatment withZnPP, a HO inhibitor, abolished partly the suppressive effect of rhEPO oncardiac hypertrophy, MDA and TNF-αlevels in myocardium wereelevated and SOD levels were lowed compared with the rhEPO treatmentgroup(p＜0.01, p＜0.05, p＜0.01). And expression of HO-1 in themyocardium was suppressed evidently in rats in rhEPO+ZnPP group(p＜0.01).Conclusion: rhEPO can induce overexpression of endogenous HO-1 in myocardium which participate at the suppressive effect ofrhEPO on cardiac hypertrophy caused by pressure-overload, rhEPO playantioxidative effect to inhibit cardiac hypertrophy via induction of HO-1.rhEPO play anti-inflammatory effect to inhibit cardiac hypertrophy,Induction of HO-1 overexpression may be one of the mechanisms of theanti- inflammatory effect of rhEPO.