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The Protection and Mechanism of N-n-butyl Haloperidol Iodide on Yocardial Ischemia-Reperfusion Injury in Rats and Cardiomyocyte Exposure to Ypoxia-Reoxygenation Induces Egr-1 Expression Involving Ca2+/PKC Pathway

Author: JiaQiangYong
Tutor: ShiGangGang
School: Shantou University
Course: Pharmacology
Keywords: Iodide, N- butyl haloperidol Ischemia-reperfusion injury Antisense oligonucleotide Early growth response gene-1
CLC: R96
Type: Master's thesis
Year: 2007
Downloads: 98
Quote: 0
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Abstract


Egr-1 is a member of the immediate-early gene family, in the role of many factors stimulate rapid expression of cell-mediated response to the external environment changes. Egr-1 in the heart rejection, lung ischemia-reperfusion (I / R) injury played a central role. Egr-1 in myocardial ischemia and reperfusion in not yet clear, therefore Task Force application Egr-1 antisense oligonucleotides observed in both overall and in vitro Egr-1 in myocardial ischemia and reperfusion and myocardial cells the role of hypoxia-reoxygenation (H / R). Found that Egr-1 plays a very important role in the cardiac I / R and myocardial cells H / R. Research group synthesized compounds iodide, N-n-butyl haloperidol (F 2 ) can inhibit ischemia-reperfusion myocardial Egr-1 mRNA and protein expression observed improvement in cardiac function. Visible F 2 by inhibiting the Egr-1 mRNA and protein expression antagonistic role of myocardial I / R injury. F 2 , reduce the role of the I / R injury by inhibiting the expression of Egr-1 F 2 with the mechanism of action? Previous studies have shown that Egr-1 in the myocardium play a very important role in the I / R studies have found that as the intracellular messengers Ca 2 , PKC participate in the regulation of Egr-1. However, the molecular mechanisms are not yet clear on Egr-1 is highly expressed in myocardial I / R. Therefore, this study mainly focus on two aspects discussed: (1) in the application of Egr-1 antisense oligonucleotides based on the addition of F 2 , Egr-1 protein expression and cardiac function by observing the changes in to explore this issue. (2) primary cultured myocardial cells H / R model, using the analog from the cardiac myocytes H / R injury in the body of myocardial I / R injury, verapamil, PKC inhibitor H7, BIM explore the Ca 2 < / sup> / PKC signaling pathway in the myocardial cells Egr-1 expression. Method 1. Myocardial ischemia-reperfusion model and experimental groups: surgical ligation of the left anterior descending branch ligation and perfusion 180min released after myocardial ischemia 60min. The rats were randomly divided into five groups: control group (Control), ischemia-reperfusion (I / R) group, solvent group (PEG), antisense oligonucleotides (AS) group, antisense oligonucleotides F 2 (AS F 2 ) group. The end of the experiment, take ligature ischemic myocardial tissue, cardiac tissue Egr-1 protein expression was determined by Western blot method; colorimetric determination of serum creatine kinase (CK), lactate dehydrogenase (LDH) activity and rat myocardial tissue myeloperoxidase enzyme (MPO) activity; thiobarbituric acid method for the determination of malondialdehyde (MDA) content; xanthine oxidase myocardial tissue superoxide dismutase ( SOD) activity. Hemodynamic monitoring during the experiment, the whole record heart rate (HR), systolic blood pressure (SP), diastolic blood pressure (DP), left ventricular systolic pressure (LVSP), left ventricular pressure maximum rate of change (± dp / dt max). 2. Cardiomyocytes during hypoxia and reoxygenation model and experimental groups: primary myocardial cell cultures, cells were grown to 5 to 7 days after their randomization: the control group (Control), hypoxia-reoxygenation (H / R) group solvent (DMSO) group, EGTA group, verapamil (VER) group, H7 and BIM groups. H / R group cells first for high-purity nitrogen saturated liquid hypoxia, placed hypoxia chamber at 37 ° C closed training 3h, and then continue in the normal medium cultured by conventional culture conditions for 1 hour, resulting in H / R injury . RT-PCR assay culture Egr-1 mRNA expression levels of myocardial cells. Western-blot assay Egr-1 protein expression in cultured myocardial cells. Results 1. AS, AS F 2 Influence and Control group than in the Egr-1 protein levels, I / R group Egr-1 protein expression significantly increased (P <0.05); than with the I / R group, AS groups, and AS F 2 group Egr-1 protein expression was significantly decreased (P <0.05). AS F of 2 group and AS group was not statistically significant (P> 0.05). 2. AS, the AS F 2 myocardial tissue MPO, SOD activity and MDA content in I / R group than in the AS, AS F 2 can effectively reduce ischemia of perfusion myocardial tissue MPO activity (P <0.05), MDA content (P <0.05), the protection of SOD activity (P <0.05). AS F of 2 group and AS group was statistically significant (P <0.05). 3. AS, AS F 2 serum LDH, CK activity of Control group than in the I / R group, serum LDH, CK activity was significantly increased (P <0.05). I / R group than the AS group, AS F of 2 group, myocardial enzyme release was significantly lower (P <0.05). AS group than AS F 2 group myocardial enzyme release was significantly reduced. 4. AS, AS F 2 hemodynamic effects of ischemia, group HR, SP, DP, LVSP, ± dp / dt max were lower, with the I / R group than the AS group the AS F of 2 group was statistically significant (P <0.05), the AS F 2 group AS group was not statistically significant (P> 0.05): reperfusion with the I / R group than AS and AS F 2 group was statistically significant (P <0.05), the AS F 2 group and AS group than statistically significant (P <0.05). 5. VER, EGTA, H7, BIM the hypoxia reoxygenation Egr-1 expression 5.1. VER, EGTA, H7, BIM cultured myocardial cells Egr-1 mRNA expression level of: RT-PCR results: H / R group and DMSO group myocardial cells Egr-1 mRNA expression levels were significantly increased compared with the Control group; H / R group than VER group, EGTA group, H7, BIM group EGR-1 mRNA of the expression was significantly reduced, the difference was statistically significant (P <0.05). 5.2. VER, EGTA, H7, BIM cultured myocardial cells Egr-1 protein levels: Western blot results showed: H / R group and DMSO group myocardial cells Egr-1 mRNA expression level was significantly higher compared to the Control group; H / R group than in the VER group, EGTA group, H7, the BIM group of Egr-1 protein expression was significantly reduced, the difference was statistically significant (P <0.05). Conclusion 1) 2 through inhibition of Egr-1 overexpression has played the role of anti-myocardial ischemia and reperfusion: F 2 in addition to play through inhibition of Egr-1 anti- myocardial ischemia-reperfusion injury, there are other mechanisms to participate. 2) Ca 2 / PKC signaling pathway involved in the high expression of Egr-1 cardiomyocytes during hypoxia and reoxygenation.

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