| Objective:The present study was designed to investigate the effect of apolipoprotein A-I mimetic peptide on obesity and post-infarcted heart function of obese rats and the possible mechanismMethods:Our study includes 2 parts:research on obesity rats and animal model of obesity with myocardial infarction.In the first part:Forty male SD rats (160-180g) at 7 weeks were ranmomly divided into four groups:1) Control+ABCT; 2) Obesity+ABCT; 3) Obesity+L-4F (HO-1 inducer); 4) Obesity+L-4F+SnMP (HO-1 inhibitor). Rats were fed with a normal diet in control group or a high fat diet in obesity groups for 8 weeks.In the second part:sixty male SD rats (160～180g) at 7 weeks were ranmomly divided into five groups:1) Control+Sham+ABCT; 2) Obesity+Sham+ABCT; 3) Obesity+MI+ABCT; 4) Obesity+MI+L-4F; 5) Obesity+MI+L-4F+SnMP. Rats were fed with a normal diet in control group or a high fat diet in obesity groups for 8 weeks.The first day after the animal model was established successfully, L-4F, an inducer of HO-1 was administered intraperitoneally every day (200μg/100g/time) for 8 weeks to Obesity+L-4F group and Obesity+MI+L-4F group maintained on a high fat diet. Animals in Obesity+L-4F+SnMP group and Obesity+MI+L-4F+SnMP group were concurrently treated with SnMP (2mg/100g/time), the inhibitor of HO-1, which was administered intraperitoneally three times a week for 8 weeks. The other groups were treated with vehicle every day for 8 weeks.In the two parts of study, we evaluated body weight every two weeks. After 8 weeks medical administration, we evaluated the heart function and structure by using the echocardiography and hemodynamic examination. At the sacrifice time, rats were anesthetized with sodium pentobarbital (1%,0.4ml/100g, i.p.). Blood samples and heart were collected. HE and Masson trichrome staining was used to observe the pathological of the myocardial tissue.The serum parameters, for example, adiponectin, insulin was measured by ELISA testing method. Real-time fluorescence quantitative PCR and Western blot was used in our research.Results:In the first part:compared with control group, Obesity+ABCT group exhibited lower activity of HO-1, increased inflammation reactive (elevated the levels of CRP, IL-6, TNFa,et al.) and oxidative stress (increased serum MDA levels and decreased the SOD levels). The obesity rats also showed the exacerbated endothelial function from the increasing ET-1, TXB2, et al. Body weight, blood pressure, blood glucose and insulin levels in Obesity+ABCT group was significantly increased. The histological examination exhibited that Obesity+ABCT group existed obvious inflammation reactive and myocyte hypertrophy. Cardiac dysfunction was evaluated by the decreasing of LVEF、LVFS、± dp/dtmax.In the second part:compared with control group, Obesity+MI+ABCT group exhibited lower activity of HO-1, increased serum CRP, IL-6, TNFa, serum MDA levels and exacerbated endothelial function from the increasing ET-1, TXB2, at al. The histological examination exhibited that Obesity+MI+ABCT group existed obvious myocardial infarction, LV fibrosis, inflammation reactive and myocyte hypertrophy. Cardiac dysfunction was evaluated by the decreasing of LVEF、LVFS、±dp/dtmax.L-4F treatment in obesity and obesity with MI rats could significantly increase the activity of HO-1, decrease the inflammation reactive and oxidative stress, could also ameliorate the cardiac function. SnMP could inhibit HO-1 activity which ascertained that the effects of L-4F treatment were related to overexpression of HO-1.Conclusions:L-4F could reduce the inflammation reactive and left ventricular remodeling, ameliorating oxidative stress and improving the endothelial function in obesity and obesity with MI rats. The possible mechanism might include the signaling pathway of L-4F-HO-1-APN-Wnt10b, Shh-PPARy, C/EBPa and L-4F-HO-1-APN-Pegl/mest. Endoplasmic reticulum stress also plays an important role in the Pathological and physiological process of obesity and obesity with myocardial infarction. |
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