| Background and ObjectiveIt is well known that cardiac hypertrophy is a common pathological result of many cardiovascular diseases as hypertension is the most important factor on left ventricular hypertrophy (LVH). Cardiac hypertrophy is the important prelude of heart failure, which can cause the high incidence rates of cardiac arrhythmia, myocardial infarction and sudden death and be generally considered as an independent risk factor of cardiovascular diseases. Therefore, the mechanism of cardiac hypertrophy is the focus of cardiovascular diseases. During the past decades, much effort has been focused on positively regulating pathways mediating cardiac hypertrophy while many researches have confirmed that protein kinase B (PKB/AKT) pathway could promote the process of cardiac hypertrophy as an example. However, more and more researches have shown that the negatively regulating hypertrophy pathways should be evaluated enough.PTEN, as a kind of antioncogene, was found in 1997. PTEN is the first antioncogene which has dual specific phosphotase activity. PTEN could play an important role in the regulation of cell growth, cell differentiation and cell cycle. Recent researches have shown that PTEN would negatively regulate cardiac hypertrophy.GSK-3βis a conservative serine/threonine protein kinase. It has two isoforms in. human tissues, that is, GSK-3 a (molecular mass-51kDa) and GSK-3β(molecular mass-47kDa). Recent researches have shown that GSK-3βhas an inhibitive function to cardiac hypertrophy.PTEN and GSK-3β, as two kinds of negative regulatory factors mediating cardiac hypertrophy, are noticeable nowadays. It may be of great significance to determine the mechanism of PTEN and GSK-3βin the process of cardiac hypertrophy, especially the relationship with AKT.We made use of the overpressure-inducing cardiac hypertrophy model in rats by abdominal aortic coarctation in this study to observe the changes of the content of PTEN and the activities of GSK-3βand AKT, to approach the role as well as the mechanism of PTEN, GSK-3βand AKT, and to investigate the effect of candesartan on the mechanism in order to get some beneficial information to treatment in the future.Materials and Methods45 adult male SD rats were used in this experiment. They were randomly divided into three groups as follows: Sham-operated rats (Sham group), overpressure-inducing rats (Model group) and overpressure-inducing rats treated with candesartan (Drug group). We made the overpressure-inducing cardiac hypertrophy model by abdominal aortic coarctation. Sham-operated rats were operated in the same way without abdominal aortic coarctation. Rats in Drug group were given 1mg/kg candesartan daily for four weeks by gastric gavage while other two groups were fed with distilled water of the same dose. All of them after four weeks were examined hemodynamic parameters by multi-lead electric physiological instrument and calculated the left ventricular mass index (LVMI), while observed morphous of the left ventricular by HE staining and evaluated the content of atrial naturiuretic factor (ANF) mRNA by RT-PCR also evaluated expression of PTEN, GSK-3βand AKT by immunohistochemistry staining.Results1 the changes of hemodynamic parameters:①Systolic blood pressure (SBP) of Model group was obviously higher than that of Sham group (139.29±5.87mmHg vs 105.31±7.48mmHg, P<0.05), SBP of Drug group was in the middle of three groups (126.03±5.06mmHg vs 105.31±7.48mmHg, P<0.05; 126.03±5.06mmHg vs 139.29±5.87mmHg, P<0.05), there were significant difference among three groups;②Left ventricular end-diastolic pressure (LVEDP) of Model group was obviously higher than that of Sham group (13.09±1.00mmHg vs 4.45±0.92mmHg, P<0.05), LVEDP of Drug group was in the middle of three groups (8.01±1.38mmHg vs 4.45±0.92 mmHg, P<0.05; 8.01±1.38mmHg vs 13.09±1.00mmHg, P<0.05), there were signifi-cant difference among three groups.2 the changes of LVMI:LVMI of Model group was obviously higher than that of Sham group (3.42±0.19mg/g vs 2.68±0.15mg/g, P<0.05), LVMI of Drug group was in the middle of three groups (3.19±0.25mg/g vs 2.68±0.15mg/g, P<0.05; 3.19±0.25 mg/g vs 3.42±0.19mg/g, P<0.05), there were significant difference among three groups.3 the observation of HE staining:Left ventricular myocardium cells had normal structure and line up in order in Sham group. The cell of Model group became hypertrophy obviously and lined up irregularly, as fibrous connective tissue of myocardium over grown. The cells of Drug group also had pathological injury but the degree of injury was less than that of Model group.4 the result of RT-PCR:The content of ANF mRNA of Model group was obviously higher than that of Sham group (0.92±0.14 vs 0.60±0.11, P<0.05), while the data of Drug group was in the middle of three groups (0.79±0.11 vs 0.60±0.11, P<0.05; 0.79±0.11 vs 0.92±0.14, P<0.05), there were significant difference among three groups.5 the results of immunohistochemistry staining:①The content of PTEN protein of Model group was obviously lower than that of Sham group (86.98±5.50 vs 118.82±5.16, P<0.05), but the data of Drug group was in the middle of three groups (102.93±3.49 vs 118.82±5.16, P<0.05; 102.93±3.49 vs 86.98±5.50, P<0.05), there were significant difference among three groups;②The content of p-GSK-3βprotein of Model group was obviously higher than that of Sham group (155.17±9.60 vs 123.67±5.66, P<0.05), but the data of Drug group was in the middle of three groups (131.02±4.88 vs 123.67±5.66, P<0.05; 131.02±4.88 vs 155.17±9.60, P<0.05), there were significant difference among three groups;③The content of p-AKT protein of Model group was obviously higher than that of Sham group (123.07±5.56 vs 80.50±5.10, P<0.05), but the data of Drug group was in the middle of three groups (86.49±4.95 vs 80.50±5.10, P<0.05; 86.49±4.95 vs 123.07±5.56, P<0.05), there were significant difference among three groups;④The content of total GSK-3βprotein and that of total AKT protein of three groups did not have any significant difference (P>0.05).6 the results of linear regression analysis:①The content of PTEN protein correlated negatively with LVMI, the content of p-GSK-3βprotein and the content of p-AKT protein respectively (r=-0.741, P<0.05; r=-0.834, P<0.05; r=-0.853, P<0.05);②The content of p-GSK-3βprotein and the content of p-AKT protein correlated positively with LVMI respectively (r=0.631,P<0.05; r=0.655, P<0.05);③The content of p-GSK-3βprotein correlated positively with the content of p-AKT protein (r=0.829,P<0.05).Conclusions1 The coarctation of abdominal aorta for four weeks may set up the model of overpressure-inducing cardiac hypertrophy in rats.2 The changes of the content of PTEN and the activities of GSK-3βand AKT can participate in the process of overpressure-inducing cardiac hypertrophy.3 The dependablity among PTEN, p-GSK-3β, p-AKT and LVMI demonstrated that PTEN and GSK-3βactivity maybe co-participate the AKT pathway and played negative roles in the process of overpressure-inducing cardiac hypertrophy.4 Candesartan can not only improve hemodynamic parameters and prevent cardiac hypertrophy, but also regulate key enzyme activities of the PTEN/AKT/GSK-3βpathway, which may be another mechanism contributing to the anti-hypertrophic effect of Candesartan.
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