【作者】 奚树刚；

【导师】 赵春燕；

【作者基本信息】 吉林大学 ， 病理学与病理生理学， 2007， 博士

【摘要】 糖尿病心肌病(DCM)作为一种与高血糖有特定关系的心肌病主要表现为心功能的降低,最终导致心力衰竭,其病理改变为细胞外基质(ECM)的聚积和心肌间质重构,其致病机制复杂。心功能的降低与心肌细胞膜离子通道、钠钙交换蛋白及肌质网钙泵功能的下降以及心肌间质纤维化等有关。因此DCM早期治疗尤为重要。龙芽葱木总皂苷(total aralosides of aralia elata, TASAE)具有改善心肌缺血、缺氧、提高抗氧化酶活性增加心肌线粒体游离钙浓度的功能,而对早期糖尿病(Diabetic Mellitus, DM)大鼠心功能和结构变化的影响,国内外尚未见报道。本研究应用心功能测定、膜片钳(patch clamp)技术,光学显微镜、电子显微镜、免疫组织化学等方法,对DM大鼠及给予龙芽葱木总皂苷后DM大鼠在体心功能、左室心肌结构、TGF-β1、CTGF以及急性分离的左室心肌细胞的L型钙通道电流(ICa-L)、瞬时外向钾电流(Ito)等进行检测,同时对各组大鼠24h尿微量白蛋白、肾功能、肾皮质TGF-β1、CTGF及肾皮质结构进行检查。结果显示:龙芽葱木总皂苷可通过L型钙通道提升DM大鼠的心功能,降低TGF-β1、CTGF在左室心肌的表达,对心肌结构的完整性具有一定保护作用。同时,还可以降低早期DM大鼠24h尿微量白蛋白含量,减少TGF-β1、CTGF在肾皮质的表达。对延缓DCM及DN的发展具有积极作用,为临床防治提供了理论依据。更多还原

【Abstract】 Diabetic cardiomyopathy (DCM) have a special relationship with high blood glucose, the decrease of left ventricle diastolic function is the main representation in early stage, and also the decrease of left ventricle systolic function would appeared accompanying with time going on, the heart failure would happened in the end. The structural changes show that the accumulation of extracellular matrix and the reconstitution of myocardial interstitium, the pathogenesis of DCM is very complicated. Besides the myocardial fibrosis, the decreased cardiac function is also related to the functions of membrane channel protein, Sarco endo reticulum calcium ATPase. Total arasolides of aralia elata (TASAE) have the function of mitigating myocardial ischemia, improving the activity of antioxidases. But the effects of TASAE on diabetic rats hearts in the early stage has not been reported yet. Meanwhile the effects of TASAE on diabetic rat’s 24h urine microalbumin and renal cortex structure were studied.Objectives:1. To observe the effects of TASAE on the hemodynamic parameters, L type calcium channel currents (ICa-L), transient outward potassium currents (Ito), TGF-β1 CTGF proteins and structures changes in diabetic rat heart during the early stages.2. To observe the effects of TASAE on renal function, 24h urine microalbumin, TGF-β1 CTGF protein and structures changes in diabetic rat kidney during the early stages .Methods:The hemodynamic parameters were detested by biological function system, ICa-L and Ito were detested by patch clamp technics and the TGF-β1 CTGF were detested by immunohistochemistry methods and ultrostructures were observed by electron microscope.Results:1. Compares with group C, LVEDP were increased and the absolute value of±dp/dtmax were decreased in group M (P<0.05). but the TASAE groups were improved (p<0.05, p<0.01); TASAE can also increase the ICa-L (P<0.01) but no effect on Ito (P<0.05), meanwhile, It can decrease the TGF-β1 and CTGF proteins expression in diabetic rat heart (P<0.01), TASAE can protect cardiac ultrostructure from damaging in early stage.2. In group M, relative kidney weight/body weight ratio and 24h urine microalbumin were increased (p<0.05), TGF-β1 and CTGF proteins expression also increased (p<0.05,p<0.01) but they were decreased in TASAE groups (p<0.05). The quantity of mesangium increased under optical microscope and glomerular basement membrane became thicken under electron microscope in group M, but they were better in TASAE group.Conclusions:1.It was discovered that different pathological changes in diabetic heart and kidney at high blood glucose state by observations of morphalogical changes and hemodynamic parameters, it showed that the models of diabetic cardiomyopathy and nephropathy were sucessed.2.It was observed that L-type calcium currents is decreased in early diabetic cardiomyocyte and TASAE can increase it,It was proved they are L-type calcium currents by Verapail and submit dose dependent.3.It was found that diastolic function is declined at 4 weeks and both systolic and diastolic function decreased at 8 weeks,TASAE can improve it through L-type calcium currents ,also submit dose dependent. 4.Persistent high blood glucose state can improve the TGF-β1、CTGF protein expression in diabetic heart and kidney during the early stage,TASAE can inhibit it and protect the structural integrity.5.TASAE can protect the structure of diabetic myocardium and glomerular basement membrane,lower the quantity of 24h urine microalbumin. According to the results, we suggested that they may have the common protective mechanism on diabetic heart and kidney by TASAE through inhibiting the TGF-β1、CTGF protein expression.更多还原