| Objective:Hypercholesterolemia(HC)is the most-recognized risk factor for ischemic heart disease(IHD).Several recent epidemiologic studies have suggested that myeloperoxidase(MPO) overexpression is a novel risk factor for IHD.However,the relationship between these two risk factors remains unknown.The present study investigated whether a diet-induced HC may result in MPO overexpression and if so,to determine whether increased MPO activity may contribute to enhanced myocardial ischemia/reperfusion(MI/R)injury in He animals.Methods:Fifty-five male Wistar rats were divided into 3 groups randomly and averagely.①Normal control group:fed with normal diets for 8 weeks.②High cholesterol diets group:fed with high cholesterol diets for 8 weeks and given DMSO by intraperitoneal injection for 3 days before ischemia reperfusion operation.③High cholesterol diets + P-ANCN dapsone group:fed with high cholesterol diets for 8 weeks and given P-ANCN dapsone(100μmol/kg,Qd)by intraperitoneal injection for 3 days before ischemia reperfusion operation.Rats were then subjected to 30 min of coronary occlusion followed by 3 hours of reperfusion.The indexes of cardiac function were derived by MS2000 system during the entire MI/R period.The blood lipoids levels were measured by using blood lipoids kit.The myocardial infarct size was measured by Evence blue and TTC(triphenyltetrazolium chloride)double staining.Myocardial apoptosis was detected by TUNEL(terminal dUTP nick end-labeling)and caspase-3 activity. The level and distribution of MPO were determined by ELISA and histochemistry respectively.Results:1.Establishment of diet-induced hypercholesterolemic rat model:Bring fed with high cholesterol diets,HC rat weighed 277±12g after 4 weeks and 423±36g after 8 weeks.The weight was higher than that of the normal control group.The TC,TG and LDL of HC rats increased more significantly than those of normal control rats.2.Higher susceptibility to myocardial ischemia-reperfusion injury of HC rats:Compared with IRI rats which were fed with normal diet,HC rats had decreased indexes of cardiac function(CI-dp/dtmax/IP;+dp/dtmax)and increased myocardial infarct size(35±2%vs. 56±6%),caspase-3 activity(P＜0.05),apoptotic index(15±3%vs.22±2%,P＜0.05).3.Increased deposition and activity of MPO at ischemia area of HC rats following IRh Compared with IRI rats which were fed with normal diet,MPO with higher activity (168±13.4 U/100 mg wet tissue vs.206±15.6 U/100 mg wet tissue,P＜0.05)deposited in myocardial tissue at ischemia area of HC rats.4.The MPO activity was positively correlated with myocardial injury indices subjected to IRI in HC rats:The myocardial infarction area was positively correlated with MPO activity and the correlation coefficient was r=0.706,P＜0.01.The apoptotic index was positively correlated with the expression of MPO active protein,r=0.739,P＜0.01.The data suggests that the enhanced susceptibility to IRI in HC rats possibly correlates with the abnormally high MOP in myocardial ischemic area.MPO possibly involves in and aggravates the IRI in HC rats.5.The IRI was alleviated after the removal of MPO in the isehemie area of HC rats which further elucidated that the increased expression and activity of MPO possibly is one of the key factors resulting in the enhanced susceptibility to IRI in HC rats:To confirm the suggestion that the enhanced susceptibility to IRI in HC rats possibly correlates with the abnormally high MOP in myocardial ischemic area in result 4 we administrated MPO scavenger,P-ANCN dapsone,to remove MPO.The results showed that after ischemia reperfusion surgery the cardiac function(CI,+dp/dtmax)was significantly improved,the infarction area was decreased,the myocardial apoptotic indexes(18±3%,P＜0.05)and caspase-3 ratio(P＜0.05)were declined in P-ANCN dapsone group compared with HC group. These evidence further suggests that MPO possibly involves in and aggravates the IRI and contributes to the increased susceptibility to IRI in HC rats.Conclusion:These results demonstrated that HC and MPO overexpression is causally related,and that anti-inflammatory agents may have significant therapeutic value in IHD patients with multiple complications such as HC.
|
PDF Full Text Request