| BACKGROUND:Diabetes and coronary heart disease are common diseases. And the incidence of ventricular arrhythmias and mortality in diabetic patients with myocardial infarction (MI) increase dramaticly. But their mechanisms are unclear. Electrical remodeling was gradually recognized related with incidence of ventricular arrhythmia in patients with MI. Electrical remodeling includes ion channel or transporter related protein expression, regulation and partner changes, which causes disturbances of heart rhythm and induces various arrhythmias. These pathophysiological remodeling occurs mainly in sodium channels, potassium channels, calcium channels, transporters, gap junction proteins, hyperpolarization activated nonselective cation channels, and so on. All these changes have prompted the extension of action potential duration, increased the dispersion of repolarization, induced abnormal conduction and loss of steady-state of cardiac electrophysiology, and then lead to fatal arrhythmias and sudden cardiac death.Diabetes mellitus is a group of chronic metabolic syndrome because of defect of insulin secretion and (or) defects of insulin, characterized by elevated blood sugar levels. Among them, type2diabetes accounts for about90%. Hyperglycemia has injured multiple organs before diabetes being diagnosed, and caused high incidence of disability and mortality. Those chronic complications are not directly caused by high blood sugar but by many biochemical changes in high blood glucose environment. The nuclear mechanism of the complications is very complicated and has not yet been fully elucidated. Cardiovascular complications of diabetes are complex and diversity. Such as complying with coronary heart disease and autonomic neuropathy in diabetic patients cause increasing incidence of sudden death and congestive heart failure and seriously affect clinical prognosis. Additionally, hyperglycemia also impairs cardiac contractility and causes electrophysiological changes, which significantly delay duration of action potential. Potassium channel current is the major current during repolarization. The impact of diabetes on action potential duration may be caused by the effects of potassium ion channel. Diabetic animal models which induced by streptozotocin or alloxan through selective destruction of pancreatic beta cells is skillful. Streptozotocin inducing diabetic model is the usual insulin deficiency model. It leads to the change of cardiac electrical and mechanical properties, which manifests as changes in action potential morphology and duration, QT interval prolongation and T wave flat on the ECG. Moreover, diabetes reduces density of transient outward potassium current and obviously changes outer membrane of endocardial myocardium. Previous study showed that the prolongation of action potential duration partly dued to outward repolarization potassium current and transient outward potassium current was reduced in diabetic cardiac myocytes.High blood glucose and MI both activate local cardiac rennin angiotensin aldosterone system (RAAS). Angiotensin Ⅱ (Ang Ⅱ) is very important in this pathological process. It can identify specific receptors through some signaling pathways, such as activating G protein, activating phospholipids enzyme C (PLC), and activating the myocardial protein kinase C (PKC). Excessive expression of PKC activates mitogen-activated protein kinase, then signals into the cell nucleus, activates the transcription gene, causes a variety of growth stimulating factor expression abnormalities like C-fos, which hinders cell protein synthesis, damages myocardial cell and leads to myocardium abnormal growing, myocardial remodeling, and cardiac function reducing. In short, Ang Ⅱ may be an important initiator of arrhythmia by affecting the function of ion channels. Valsartan, as a kind of specific AT1receptor competitive antagonist, prevents Ang Ⅱ through AT1transmembrane amino acids and then blocks the Ang Ⅱ-induced biological negative effects. A few studies have identified that valsartan can improve local abnormal conduction of atrial fibrosis, reduce the release of norepinephrine, improve atrial repolarization heterogeneity, and inhibit electrical remodeling. Moreover, it also can dramatically reduce the incidence of type2diabetes. Whether valsartan impact ventricular electrical remodeling in diabetic patients with MI or not is unknown. In this study, we evaluate the expression profile following MI in a diabetic model, to explore the effects of valsartan on the expression of transient outward potassium channel (Kv1.4, Kv4.2, Kv4.3) in the left ventricle of diabetic rabbits after experimental MI.AIM:To explore the expression of the transient outward potassium channel in diabetic rabbits after experimental MI and valsartan intervention study.METHODS:1. New Zealand rabbits were randomly divided into diabetes+MI group(Group DM+MI, n=14), sham operation diabetic group(Group DM, n=14) and non-diabetic sham operation group(Group sham, n=14). And then diabetic rabbit model was produced. High fat and high calorie mixed diet were feeded for2months and then ALX (80mg/kg, Alloxan) was injected through auricular vein. The standards of diabetic animals are the concentrations of fasting blood glucose>14mmol/L by2consecutive analyses72h and7d after injection. If not done, then repeat injection ALX (50mg/kg) above methods. After diabetic model was established, general feed was given for4months in individual cages. MI model was created by ligature of the left anterior descending coronary artery. It was confirmed by regional cyanosis and electrocardiographic change (more than two ST segment elevations of0.1mV or higher and7days later the Q wave appears). After routine feeding for2months, the animals were sacrificed and heart was isolated. Left ventricle tissue around infarction aera was rinsed in saline and DEPC water to remove excess blood, snap-frozen in liquid nitrogen, and stored at-80℃. Real-time quantitative PCR and western blot were used to observe the expression of Kv4.2, Kv4.3, and Kv1.4in ventricle.2. Sixty successful models of New Zealand rabbits were randomly divided into six groups:the placebo Group (Group P, n=10), low dose Group (Group L, n=10), moderate dose Group (Group M, n=10), high dose of medication6weeks Group (Group H1, n=10), high dose of medication8weeks Group (Group H2, n=10) and high dose of medication10weeks (Group H3, n=10).The treatment Groups were intragastricly administrated valsartan for6to10weeks. Among them, the Group L give5mg/(kg-d) valsartan for6weeks; Group M give10mg/(kg·d) valsartan for6weeks; Group H1give3Omg/(kg-d) valsartan for6weeks; Group H2give30mg/(kg·d) valsartan for8weeks; Group H3give30mg/(kg·d) valsartan for10weeks. Group P give normal saline instead of valsartan for6weeks. All rabbits were sacrificed6weeks,8weeks or10weeks respectively after the procedure. Then heart was isolated and left ventricle tissue around infarction aera was carefully excised and rinsed in saline and DEPC water to remove excess blood, snap-frozen in liquid nitrogen, and stored at-80℃. Real-time quantitative PCR and western blot were used to observe the expression of Kv4.2, Kv4.3, and Kv1.4in ventricle.RESULTS:1. Compared with Group sham, the expression levels of Kvl.4mRNA in both Group DM+MI and Group DM were increased significantly, while the expression levels of Kv4.2and Kv4.3mRNA were decreased significantly (P<0.05). The expression levels of Kv4.2and Kv4.3mRNA in Group DM+MI rabbit ventricle were significantly lower than the Group DM (P<0.05). But the expression of Kvl.4mRNA did not change significantly (P>0.05).2. Compared with Group sham, the expression levels of Kvl.4protein in both Group DM+MI and Group DM were increased significantly, while the expression levels of Kv4.2and Kv4.3protein were decreased significantly (P<0.05). The expression levels of Kv4.2and Kv4.3protein in Group DM+MI rabbit ventricle were significantly lower than the Group DM (P<0.05). But the expression of Kv1.4protein did not change significantly (P>0.05).3. Compared with Group P, the expression levels of Kv1.4mRNA of each treament group were decreased significantly and the expression levels of Kv4.2and Kv4.3mRNA were increased significantly (P<0.05). The expression levels of Kv4.2and Kv4.3mRNA in Group M,Group H1. Group H2or Group H3were significantly higher than Group L (P<0.05), while Kv1.4did not significantly change (P>0.05). The expression levels of Kv4.2and Kv4.3mRNA in Group H3were significantly higher than Group H1(P<0.05), and Kvl.4did not significantly change (P>0.05). But the expression of Kv4.2, Kv4.3and Kv1.4mRNA levels between Group H1and Group H2showed no significant change (P>0.05).4. Compared with Group P, the expression levels of Kv1.4protein of each treament group were decreased significantly and the expression levels of Kv4.2and Kv4.3protein were increased significantly (P<0.05). The expression levels of Kv4.2and Kv4.3protein in Group M,Group H1. Group H2or Group H3were significantly higher than Group L (P<0.05), while Kv1.4did not significantly change (P>0.05). The expression levels of Kv4.2and Kv4.3protein in Group H3were significantly higher than Group H1(P<0.05), and Kv1.4did not significantly change (P>0.05). But the expression of Kv4.2, Kv4.3and Kv1.4protein levels between Group H1and Group H2showed no significant change (P>0.05).5. Compared with group P respectively, the fasting glucose levels in valsartan treatment groups at the end-stage of the experiment decreased significantly (P<0.05).CONCLUSIONS:1. The expression of transient outward potassium channel changed obviously in diabetic rabbits after experimental MI. And these suggested there existed electrical remodeling, which probably increased the susceptibility of ventricular arrhythmias after MI with diabetes.2. Valsartan treatment partly improved expression of transient outward potassium channel and inhibited electrical remodeling, which was likely to reduce the incidence of ventricular arrhythmias in diabetes after experimental MI.3. Polonged valsartan treatment was helpful to decrease fasting blood glucose in diabetic rabbits with experimental MI.4. The role of valsartan presented dose and dependent. In addition to these, long-term treatment was more effective. |
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