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The Influence of Fenofibrate on Energy Metabolism of the Failing Heart

Author: LuoShiZuo
Tutor: LiPing
School: Nanchang University
Course: Internal Medicine
Keywords: Heart Failure Fenofibrate Energy metabolism Isoproterenol
CLC: R541.6
Type: Master's thesis
Year: 2011
Downloads: 16
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Abstract

[Objective] treatment of heart failure has made tremendous progress, mortality was significantly reduced, but still insufficient to control the progress of heart failure, studies have shown that myocardial energy metabolism in which played an important role, the purpose of this experiment is to explore isoproterenol-induced peroxisome proliferator-activated receptor a (PPAR a) ligand fenofibrate and myocardial energy metabolism in rats with chronic heart failure process. [Method] (a) Construction of a rat heart failure model: SD rats were randomly divided into four groups, the control group of 10 heart failure group (n = 20), weighing 200-300g (1) control group: daily subcutaneous injected with normal saline for a period of four weeks; (2) ISO (isoproterenol, ISO), a small dose group: ISO1 daily subcutaneous dose of 2 mg / kg / d; (3) in the dose ISO Group: day subcutaneous injection of ISO1 time, a dose of 2.5 mg / kg / d; (4) high-dose ISO Group: ISO1 times daily subcutaneous injection, the dose for the weekend to assess 3mg/kg/d, 4 rats survival through the heart ultrasonography and measurement of serum BNP values ??to calculate the heart body mass index evaluation of the four groups of rats cardiac function, and explore best dose rat heart failure model. (B) The drug intervention research: male SD rats 30, weighing 200-300g were randomly divided into 3 groups (n = 10): control group: regular feeding, daily subcutaneous injections of normal saline; 2, non- the fenofibrate protection group (FF): containing conventional feeding FF group was given non Norbert suspension gavage, dose 100mg/kg/d (dose Reference) for four consecutive weeks, given after subcutaneous injection of ISO (2.5mg/kg/d) a period of four weeks; ISO injury group: conventional feeding given subcutaneous injection of ISO (2.5mg/kg/d) a period of four weeks. Evaluation of cardiac function echocardiography: 2, 3, and 4 weeks the rats to 0.3% solution of sodium pentobarbital anesthetized by intraperitoneal injection (10ml/kg) reserve skin, ultrasonic testing, detection of left ventricular end-diastolic diameter (LVEDD ), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (FS). The serum BNP: 2,3,4 weeks pumping carotid artery intubation take rats eye to take a blood test BNP. 4 weekend, all rats were under general anesthesia in the carotid artery intubation blood was centrifuged to obtain serum, anatomy of the heart, each group select the part of the heart specimens were fixed in 10% formalin for 24 h the conventional drawn, dehydration, paraffin buried and every lmm cross-section along the long axis of the left ventricle was cut three sections, HE staining was observed under an optical microscope, I rats myocardial tissue stored in liquid nitrogen. Myocardial biopsy OUTCOME MEASURES: Myocardial Pathological changes observed under an optical microscope. Heart weight index: heart with cold saline to wash away residual blood, cut around the connective tissue and blood vessels, water filter paper weighing heart wet weight. Heart weight index = heart weight / body weight. Serum: ELISA assay serum BNP and reference the free fatty acid kit was used to detect serum free fatty acid (FFA) content. Myocardial tissue: reference to free fatty acid kit detection of free fatty acid content in myocardial tissue spectrophotometric detection of myocardial tissue lactate and pyruvate content, Western blot detection of PPARα protein expression of UCP2 in islets of. [Results] 1. Establishment of the injected dose for heart failure model rats died 14 3mg/kg/d group 4 weekend, the injection dose of 2 mg / kg / d rats died, 2.5 mg / kg / d group 4 weekend The rats died two large, low-dose group survival rates were 30%, 90% and 100%. Compared with the control group, the ISO model LVEDD, LVESD, BNP and cardiac mass index were higher, LVEF, FS lower than the control group (comparison between groups, P lt; 0.01). ISO model LVEDD, LVESD, BNP and heart weight index with increasing ISO dose increases (comparison group, P lt; 0.01), LVEF, FS increase as the ISO dose reduced (group P all lt; 0.05), 3mg/kg/d high-dose group compared with 2.5 mg / kg / d, although the degree of heart failure is more serious, but the survival rate was significantly reduced heart failure model successfully established ISO subcutaneous dose of 2.5 mg / kg / d more appropriate. Changes in cardiac structure and cardiac function after 4 weeks, FF protection group ISO Injuries Group LVEDD, LVESD was significantly greater than the control group (P lt; 0.05), compared with the FF protection group ISO Injuries Group LVEDD, LVESD obvious increased (P lt; 0.05); FF protection group ISO Injuries Group LVEF, FS was significantly lower than the control group (P lt; 0.05), compared with the FF protection group, ISO Injuries Group LVEF, FS significantly decreased (P lt; 0.05) 3. the myocardial pathological change with the control group, compared to the FF protection group ISO Injuries Group myocardial cell hypertrophy, eosinophilic degeneration and (or) necrosis, lesions were focal or diffuse distribution of part of the myocardial cells, part of the myocardial interstitial connective tissue hyperplasia, proliferation of connective tissue was streak lighter FF protection group cardiomyocyte hypertrophy and myocardial interstitial connective tissue hyperplasia compared with the ISO group. 4. Heart weight index comparing FF protection group with ISO injury group heart weight index (3.16 ± 0.12,3.58 ± 0.08) and the control group (2.13 ± 0.15), there were significant differences (all P lt; 0.05), and FF protection group ISO injury group compared heart weight index was significantly higher (P lt; 0.01). FF protection group ISO of serum BNP damage serum BNP (1.79 ± 0.09,4.86 ± 0.12) with the control group (0.39 ± 0.03), there were significant differences (all P lt; 0.01), FF protection group Compared ISO injury serum BNP was significantly higher (P lt; 0.01). 6 serum FFA and myocardial FFA FF protection group with the ISO injury serum FFA and myocardial FFA were significantly higher than that of the control group (all P lt; 0.01), compared with the FF protection group ISO injury serum FFA and myocardial FFA obvious higher (all P lt; 0.05). 7. Myocardial tissue lactate, pyruvate FF protection group with the ISO-injury group myocardial lactate, pyruvate were significantly higher than that of the control group (all P lt; 0.01), compared with the FF protection group ISO damage myocardial lactate, pyruvate significantly higher (all P lt; 0.05). The myocardial tissue PPARα FF protection group with ISO myocardial tissue injury group PPARα (614.13 ± 87.08.160.34 ± 14.12) and the control group (1586.69 ± 93.44), there were significant differences (all P lt; 0.01), and FF protection ISO damage serum PPARα was significantly lower (P lt; 0.01) 9. myocardial tissue UCP2 FF protection group with ISO myocardial tissue injury group, the UCP2 (637.28 ± 73.14,1217.09 ± 81.88) and the control group (435.56 ± 63.18) compared showed significant differences (all P lt; 0.01), compared with the FF protection group, ISO damage serum UCP2 was significantly higher (P lt; 0.01). [Conclusion] in the progression of chronic heart failure, the presence of myocardial fatty acid utilization disorders and mitochondrial uncoupling of oxidative phosphorylation leading to reduced energy generation. Peroxisome proliferation receptor activator fenofibrate by upregulating the expression of myocardial PPARα, reduce serum free fatty acid content, further reduce myocardial UCP2 expression thereby improving the energy metabolism of the heart failure myocardium, inhibition of ventricular remodeling has a protective effect on heart failure, myocardial.

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