Study On Effects Of Tongluo Capsule On Myocardial Lesion In Diabetic Rats And Its Mechanism

Diabetic cardiomyopathy (DCM) is a common long-term complication of diabetes mellitus and a special cardiomyopathy. The morphological characteristics of DCM are myocardial extracellular matrix (ECM) accumulation and myocardial interstitial remodeling. The onset of DCM is the result of combined action of multiple factors, including glucose metabolic disturbance, production and release of cytokine factors and growth factors. Among these factors, the enhanced activity of rennin-angiotensin system(RAS)in myocardium tissue has been considered as an important factor in pathogenesis of DCM. The potential mechanism of how the activity enhancing RAS cause myocardiac pathological change is not clear. Such a deep research has not appeared so far.Indirect and direct evidences have indicated that connective tissue growth factor (CTGF),a recently identified new growth factor, acts as a downstream mediator of TGF-βprofibrotic effects. CTGF only mediates the profibrotic effects of TGF-βand does not affect the anti-inflammatory and anti-proliferative effects of TGF-β. Therefore, CTGF may serve as a new therapeutic target for DCM. However, the expressive condition of CTGF in the myocardium in diabetic rats induced by streptozotocin (STZ),and the effects of CTGF on ECM accumulation as well as the expressive impact of RAS towards CTGF has not been determined.There are no effective therapies for DCM till now in the modern medicine. In recent years, the clinical and experimental study on preventing and treating DCM of traditional Chinese medicine has shown the promising prospecct. TongLuo capsule (TL capsule) is composition of traditional Chinese medicine, and it can obviously inhibit ECM accumulation of diabetic nephropathy. However, effects of TL capsule on myocardium in diabetic rats and its mechanism has not been covered.The aim of this study is to investigate the the protective effects of Tong Luo capsule on myocardial lesion in diabetic rats and its mechanism by researching the RAS effects on CTGF gene expression in myocardium of diabetic rats, as well as the relation of these cytokine factors on ECM accumulation. We anticipate determining the new effects of RAS on CTGF mRNA expression and definituding the relation of CTGF mRNA expression on ECM accumulation and clarifying the proceeding mechanism of the activity enhancing RAS with ECM accumulation and providing experimental basis for determining a new therapeutic target for DCM.The research methods applied in this study include the myocardiac morphological changes, immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). The parameters evaluation includes:①the myocardial structure in diabetic rats and the protective effects of TL capsule;②the impact of TL capsule on the synthetic mechanism of ECM components;③the effect of TL capsule on ACE activities and AngⅡcontents in myocardium;④the effect of TL capsule on CTGF mRNA expression in diabetic myocardium.The main results are as follows:1. At the end of 12 weeks in STZ-induced diabetic rats, diabetic rats showed diabetic symptoms and metabolic disturbance of blood glucose. Administration of TL capsule improved general status and metabolic disturbance of blood glucose in diabetic rats. 2.. The myocardial structures in diabetic rats were obviously altered at the end of 12 weeks. The alterations included an increased in the number ofl fibrocyte in myocardiac interstitium, PAS positive substances were markedly deposited and the contents of fibronectin (FN), collagenⅠ(ColⅠ) and collagenⅢ(ColⅢ) as well as the ratio of ColⅠ/ColⅢwere increased (P<0.01, P<0.05). The pathological changes in myocardium were obviously alleviated by treatment with TL capsule.3. At the end of 12 weeks in diabetes, ACE activities and AngⅡcontents in myocardium of diabetic rats were increased, after administration of TL capsule for 12 weeks, the ACE activities and AngⅡcontents were obviously reduced.4. CTGF mRNA expression in myocardium of diabetic rats was increased at the end of 12 weeks in diabetes. After treatment with TL capsule for 12 weeks, CTGF mRNA expression was significantly decreased.The main conclusions of this study are:1. Administration of TL capsule improved general status and metabolic disturbance of blood glucose in diabetic rats.2. The myocardial structures in diabetic rats were obviously altered and increased ECM components in myocardium at the end of 12 weeks in diabetes. The changes were obviously alleviated after treatment with TL capsule.3. Administration of TL capsule for 12 weeks, the ACE activities and AngⅡcontents in diabetic myocardium were obviously reduced.4. After treatment with TL capsule for 12 weeks, CTGF mRNA expression in diabetic myocardium were significantly decreased.The main creative results are that TL capsule has the action of suppressing synthesis of ECM in myocardium of diabetic rats, the myocardial changes were obviously alleviated and the ACE activities and AngⅡcontents in diabetic myocardium were obviously reduced by treatment with TL capsule. The actions may be related with down-regulating CTGF mRNA expression. These findings provide experimental basis for preventing and treating of the diabetic cardiomyopathy.