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Mechanism of Candesartan Improving Insulin Resistance in Spontaneously Hypertensive Rats and C2C12Myotubes

Author: LiFan
Tutor: ZengQiang
School:
Course: Elderly patients with cardiovascular
Keywords: Candesartan insulin resistance angiotensin II reactive oxygenspecies the transcription factor NF-E2related factor2
CLC: R544.1
Type: PhD thesis
Year: 2013
Downloads: 110
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Abstract


Objective:1. To investigate the effects of candesartan on insulin resistance inspontaneously hypertensive rats and its possible mechanisms.2. To investigate the mechanisms of candesartan on prevention ofangiotensin II to damage the insulin signal pathways in C2C12myotubes.Methods:1. The experimental animals were divided into control group, modelgroup, the high-dose group of candesartan (0.8mg/kg body weight perday) and the low-dose group of candesartan (0.4mg/kg body weight perday). Animals were sacrificed at8weeks. Blood sample were collectedto determine the serum angiotensin II, fasting blood glucose (FBG),fasting serum insulin (FINs). The insulin resistance index (HOMA-IR)was calculated by the FBG and FINs. Skeletal muscles were collectedto detect the content of reactive oxygen species (ROS), mRNA expressionof protein kinase (Akt) and p-Akt protein expression. The expressionof angiotensin II type1receptor (AT1R) and angiotensin II type2receptor (AT2R) in skeletal muscle cells were detected byimmunohistochemical method.2. The mature C2C12myotubes were divided into the following5groups:control group, model group, low-dose group of candesartan (0.1μM),mid-dose group of candesartan (1μM), high-dose group of candesartan(10μM). All the groups were treated with angiotensin II (0.1μM)except the control group. Determine the ROS expression and the uptakeof2-NBDG in C2C12myotubes. Detected the mRNA expression of phosphatidylinositol kinase (PI3K p85), insulin receptor substrate1(IRS-1), Akt, transcription factor NF-E2-related factor2(Nrf2) andglucose transporterbody4(GLUT-4) and their protein expression in thecells.Results:1. At8weeks, compared with the control group rats, the blood pressure,FINs, HOMA-IR, expression of AT1R and ROS in skeletal muscle of modelgroup rats were significantly increased (P<0.01). Compared with modelgroup rats, blood of the rats treated with candesartan decreasedsignificantly (P<0.01).Their FINs, HOMA-IR, expression of ROS inskeletal muscle also decreased (P<0.01, P<0.05). Expression of AT1R,AT2R, mRNA of Akt and p-Akt protein were increased significantly inthese two groups of rats (P<0.01, p<0.05).2. Compared with the control group, the ROS expression in C2C12myotubes was significantly increased in model group (P <0.01). Thecells uptake2-NBDG significantly reduced (P <0.01), and theexpression of mRNA of Nrf2, Akt, IRS-1and GLUT-4reduced significantly(P <0.05, P <0.01), Nrf2, p-Akt, p-IRS-1and GLUT-4protein expressionlevels were also significantly lower (P <0.05, P <0.01). The ROSexpression in the high-dose group of candesartan cells decreasedsignificantly than the model group cells (P <0.05). Their cellularuptake of2-NBDG increased significantly than the model group (P <0.05).Compared with model group, cells of mid-dose group of candesartan andhigh-dose group of candesartan expressed the mRNA of Nrf2, PI3K p85,IRS-1and Akt significantly upregulated (P <0.05, P <0.01), at the sametime, expression levels of Nrf2, PI3K p85, p-IRS-1, P-Akt protein werealso significantly increased (P <0.05, P <0.01).Conclusion:1. Candesartan can significantly reduce blood pressure, serum insulin and the generation of ROS in skeletal muscle tissue of SHR, as wellas increase the expression of Akt mRNA and P-Akt protein in skeletalmuscle cells of SHR. These results indicate that candesartan reversesAng II induced insulin resistance by its specific binding with AT1R.2. In C2C12myotubes, angiotensin II affecting the normalphysiological effects of insulin and resulting in insulin resistanceby down-regulating the expression of ISR-1, PI3K, Akt, GLUT-4, whichthe important reaction components of the insulin molecule signalpathway. Angiotensin II may down-regulate the expression of Nrf2inC2C12muotubes to increase production of ROS and oxidative stress incells, and further damage to the insulin molecule signaling pathwayand increased insulin resistance. Candesartan can reduce the effectof angiotensin II on the insulin signal transduction pathway andimprove angiotensin II-induced insulin resistance by directlycombined with AT1R.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Abnormal blood pressure > Hypertension
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