| Objective: Along with the improvement of people’s living standards and changes in diet,obesity has become more and more popular,affecting the quality of human life and life span severely.According to the statistics,the incidence of obesity in women is much more than in men.Obesity often leads to the metabolic syndrome(MS)with metabolic disturbance of protein,lipid,carbohydrates,characterized by abdominal obesity,insulin resistance,sugar and lipid metabolic abnormalities,and hypertension.MS can cause multi-organs damage and a series of diseases,such as dementia,gout,fatty liver,platelet activation,increased blood viscosity,diabetes,arterial stenosis,and coronary heart disease,etc.Numerous factors like obesity,hypertension,lipid metabolism disorders,hyperglycemia,and insulin resistance,alone or in combination,can cause and aggravate abnormality of the cardiac structure and function.Obese Zucker rats(OZR),an autosomal recessive mutation on chromosome 5 resulting from missense mutation of Gln to Pro residue at position 269 of the leptin receptor,is characterized by obesity and MS,and is recognized as an ideal model of human obesity and MS.Chronic intermittent hypobaric hypoxia(CIHH)refers to the intermittent exposure of tissues or body to hypobaric hypoxia,while the rest of time in a normobaric normoxia environment.A large number of studies have shown that CIHH,similar to ischemic preconditioning,has obvious cardiac protection,enhancing resistance of myocardial ischemia/reperfusion(I/R)injury.Our recent study found that CIHH can protect cardiac function through improve the antioxidant capacity of the heart in fructose-induced MS rat model,and reduce the incidence of cardiac arrhythmia caused by ischemia/reperfusion(I/R).Until now,the effect of CIHH on the heart of MS induced by leptin receptor deficiency,especially on female animals,is not elucidated.The aim of present study is to explore the effect of CIHH on heart against I/R injury in female Zucker rats using functional and biochemical methods,and the underlying mechanism.Methods:The adult female lean Zucker rat(LZR)and obese Zucker rats(OZR)were randomly divided into 4 groups: LZR group,LZR + CIHH group,OZR group,and OZR+ CIHH group.LZR + CIHH,OZR + CIHH rats were put into a hypobaric chamber to get 28 days CIHH exposure mimicking 5000 m high altitude,6 hours per day,while in the rest time the rats were placed in the normal oxygen environment.The LZR and OZR animals were kept under the same environmental conditions as the CIHH rats,with free access to water and food,but without exposure to CIHH.All rats were fed standard diet.The rat was anesthetized with Urethane injection intraperitoneally(50mg per kg body weight)and was fixed on back lying position.After thoracotomy,the hearts were quickly excised and mounted on a Langendorff isolated heart perfusion apparatus.A water-filled latex balloon connecting to a pressure transducer was introduced into the left ventricle through the atria to record isovolumic left ventricular pressure.The functional parameters of isolated rat heart,including left ventricular developed pressure(LVDP),left ventricular end diastolic pressure(LVEDP),maximum/minimum rates of developed left ventricular pressure(LVdp/dtmax/LVdp/dtmin),coronary flow(CF)and heart rate(HR)were recorded under the basical condition and during I/R continuously.After 20-minstabilizationwith K-H solution perfusion,the hearts were subjected to 30 min no-flow global ischemia followed by 60-120 min of reperfusion.The cardiac function was recorded before,during,and after I/R.The heart was soaked in 37 ℃ perfusate during the entire ischemia period to maintain constant temperature of the heart.In order to investigate the mechanism underlying the cardioprotective effect of CIHH,5μmol/L GLI,a unspecific KATP channel antagonist,100μmol/L 5 – HD,a mitochondria KATP channel antagonist,and 20μmol/L ATRA,a blocker of Mitochondrial permeability transition pore(MPTP)opening,were pretreated before ischemia or reperfusion.At the end of the experiment,the heart was rapidly removed from the Langendorff apparatus.Some hearts were sliced to determine the infarct size by TTC reagent,while other hearts were frozen in liquid nitrogen and stored at-80℃ for biochemical assay.The activity of myocardial superoxide dismutase(SOD)was assessed by xanthine oxidase method,and content of malondialdehyde(MDA)were measured by thiobarbituric acid method.Results:1Under the basal condition,there were no significant difference of the cardiac functional parameters among LZR and OZR rats(P>0.05).After cardiac I/R,LVDP,LVdp/dtmax and LVdp/dtmin were increased(P<0.05),while LVEDP was decreased(P<0.05)in LZR rats compared with OZR rats.There was no significant difference of CF between the two groups(P> 0.05).The myocardial infarction area was decreased significantly in LZR ratscompared with OZR rats(P<0.01).The SOD activity was significantly higher(P<0.05),while MDA content was significantly lower in LZR rats than those in OZR rats(P<0.05).2 Under the basal condition,there were no significant difference of the cardiac functional parameters among LZR and LZR+CIHH rats(P>0.05).After cardiac I/R,LVDP,LVdp/dtmax,LVdp/dtmin and CF were increased(P<0.05),while LVEDP was decreased in LZR+CIHH rats(P<0.05)compared with LZR rats.The myocardial infarction area was decreased significantly in LZR+CIHH rats(P<0.01)compared with LZR rats.The SOD activity was increased(P<0.01),while the MDA content was decreased significantly(P< 0.05)in LZR+CIHH rats compared with LZR rats.3 Under the basal condition,there were no significant difference of the cardiac functional parameters among OZR and OZR+CIHH rats(P>0.05).After cardiac I/R,LVDP,LVdp/dtmax and LVdp/dtmin were decreased(P<0.05,or P<0.01),while LVEDP was increased in OZR+CIHH rats(P<0.05),compared with OZR rats.There was no significant difference of CF and the myocardial infarction area between the two groups(P>0.05).The SOD activity was decreased(P<0.05),while MDA content was increased significantly(P<0.05)in OZR + CIHH rats compared with OZR rats.4Pretreatment with GLI(5μmol/L)immediately at the beginning of reperfusion,the cardiac functional parameters such as LVDP,LVdp/dtmax,LVdp/dtmin and CF were decreased(P<0.05,or P<0.01),while LVEDP was increased(P<0.01)compared with LZR+CIHH without GLI pretreatment.After GLI pretreatment,the myocardial infarction area was bigger(P<0.05),the SOD activity was lower(P<0.05),while MDA was higher(P<0.05),than LZR+CIHH without GLI pretreatment rats.5Pretreatment with 5-HD(100μmol/L)before ischemia,the cardiac functional parameters after I/R such as LVDP,LVdp/dtmax,LVdp/dtmin and CF were decreased(P<0.05,or P<0.01),while LVEDP was increased(P<0.01)compared with LZR+CIHHwithout 5-HD pretreatment.After 5-HD pretreatment,the myocardial infarction area was bigger(P<0.05)and the SOD activity was lower(P<0.05),while MDA was higher(P<0.05),than LZR+CIHH without 5-HD pretreatment rats.6Pretreatment with ATRA(20μmol/L)immediately at the beginning of reperfusion,the cardiac functional parameters such as LVDP,LVdp/dtmax,LVdp/dtmin and CF were decreased(P<0.05,or P<0.01),while LVEDP was increased(P<0.05)compared with LZR+CIHH without ATRA pretreatment.After ATRA pretreatment,the myocardial infarction area was bigger(P<0.05)and the SOD activity was lower(P<0.05),while MDA was higher(P<0.05),than LZR+CIHH without ATRA pretreatment rats.Conclusion:There is no significant difference of cardiac function between female LZR and OZR under normal basic condition,while the tolerance to cardiac I/R injury is higher in LZR than OZR.CIHH treatment simulating 5000 m altitudeinduces cardiac protection in LZR,but produces cardiac damage in OZR.The protective effect on LZR heart against I/R injury might be related to opening of ATP-sensitive potassium channels in plasmalemma and mitochondria membrane,inhibition of mitochondrion permeable transform pore opening,and improvement of myocardial anti-oxydation. |
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