多沙唑嗪干预对α_1肾上腺素能受体抗体阳性糖尿病大鼠心肌的保护作用

Study on Protective Mechanism of the Treatment of Doxazosin on Myocardium in α1-adrenergic Receptors Antibody Mediated Diabetic Rats

目的:探讨多沙唑嗪干预对α1肾上腺素能受体自身抗体(α1R-Ab)阳性糖尿病(DM)大鼠心肌转化生长因子β1(TGF-β1)和Ⅰ型胶原表达的影响及其心肌保护作用。方法:Wistar大鼠分为5组:A组(正常对照组,n=10)、B组(DM模型组,n=10)、C组(DM+多沙唑嗪干预组,n=10)、D组(α1R-AbDM组,n=8)和E组(α1R-AbDM+多沙唑嗪干预组,n=8)。腹腔注射链脲佐霉素(STZ)复制T2DM模型。造模成功后,D组和E组于当周、第4、8、12、16周尾静脉注射α1R-Ab注射液(100μg/100g),建立α1R-AbDM模型。C组和E组均从注射α1R-Ab起每日给予多沙唑嗪0.36mg/Kg灌胃,持续16周。A组不予任何处理。16周后处死各组大鼠,取左室心肌组织常规病理切片和超薄切片,采用免疫组化检测左室心肌TGF-β1和Ⅰ型胶原表达量,电镜观察心肌超微结构。结果:A组大鼠心肌TGF-β1和Ⅰ型胶原表达明显低于B、C、D、E组(均P<0.01),C组心肌TGF-β1和Ⅰ型胶原表达低于B组(P<0.05),E组心肌TGF-β1和Ⅰ型胶原表达亦明显低于D组(P<0.05);电镜下,A组心肌未见明显异常;D组心肌线粒体减少,排列紊乱,呈空泡变性,间质胶原增生,微血管基底膜增厚;而E组心肌病变较D组明显减轻;C组心肌病变亦较B组明显减轻。结论:多沙唑嗪可通过抑制α1R-Ab阳性DM大鼠心肌组织中TGF-和Ⅰ型胶原表达,减轻DM大鼠心肌间质纤维化,保护心肌。

Objective: To observe the effects of doxazosin on the expression of transforming growth factor β1(TGF-β1) and type Ⅰ collagen fiber in autoantibodies against α1-adrenergic receptors (α1R-Ab) positive diabetic rats, and to investigate the protective mechanism of doxazosin on cardiomyopathy of diabetic rats. Method: Wistar rats were divided into five groups: group A (normal control group, n=10), group B(diabetic non-mediated group, n=10), group C(diabetic doxazosin intervention group, n=10), group D(diabetic α1R-Ab mediated group, n=8), group E(diabetic both α1R-Ab mediated and doxazosin intervention group, n=8).After establishment of diabetes model with streptozocin, group D and group E were syringed α1R-Ab(100μg100g) by tails vein at 0, 4, 8, 12 and 16 weeks. Doxazosin (0.36mgKg) was administered for 16 weeks per day in group C and group E and group A does not intervene. Pathological changes in the myocardium were observed by light microscope and electron microscope. Expression of TGF-β1 and typeⅠ collagen fiber in myocardium of left ventricle were detected by immunohistochemical staining. Results: Expression of TGF-β1 and typeⅠ collagen fiber on myocardium in group A were lower than group B, group C, group D and group E (all P<0.01). Expression of TGF-β1 and typeⅠ collagen fiber in group C were lower than group B (P<0.05). Expression of TGF-β1and typeⅠ collagen fiber on myocardium in group E were lower than group D (P<0.05). Group A showed no obvious abnormalities.Myocardial pathological changes in group D were the most serious, mitochondrial reduce, arrangement disorder, show vacuolar degeneration, interstitial collagen hyperplasia, microvascular basement membrane thickening. Compared with group D, the cardiomyopathy of group E showed a decreased damage. Conclusion: Doxazosin can suppress expressions of TGF-β1 and type Ⅰcollagen fiber in myocardium of diabetic rats with α1R-Ab mediated, thus resulting in the alleviate of myocardial fibrosis and protective effect of myocardium in diabetic rats.