在1型糖尿病小鼠模型中，缺乏Rac1阻断NADPH氧化酶活化，抑制内质网应激反应，从而抑制心肌重塑
文献 Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes. 于 2010年 发表在 Diabetes 原文链接
Abstract：
OBJECTIVE:
Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes.
RESEARCH DESIGN AND METHODS:
Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose.
RESULTS:
In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose-induced ER stress was inhibited by blocking Rac1 or NADPH oxidase.
CONCLUSIONS:
Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy.
摘要：
背景：
我们最近的研究表明Rac1和NADPH氧化酶活化参与短期糖尿病心肌细胞凋亡过程。本研究旨在探讨慢性糖尿病心肌重构中RAC 1缺失和NADPH氧化酶失活是否阻碍心肌重塑。
方法：
心肌细胞特异性RAC-1基因敲除小鼠及野生型小鼠经注射链脲佐菌素诱发糖尿病。在另一个单独的实验中，在野生型糖尿病小鼠的饮用水中添加溶剂或apocynin。患糖尿病2个月后，观察小鼠心肌肥大、纤维化、内质网应激反应、炎症反应及心肌功能的变化。分离成年大鼠心肌细胞，用高糖刺激培养。
结果：
在糖尿病小鼠心脏中，RAc 1基因敲除或apocynin治疗可抑制NADPH氧化酶的激活、其亚基的表达和活性氧的产生。伴随着促纤维化基因和肥大基因的高表达，糖尿病小鼠心肌胶原沉积和心肌细胞截面积显著增加。Rac 1或apocynin缺乏可缓解心肌纤维化和心肌肥大，从而改善心肌功能。这些作用与糖尿病中心脏ER应激标志物的表达和炎症反应的正常化有关。在培养的心肌细胞中，通过阻断Rac 1或NADPH氧化酶，可以抑制高糖诱导的ER应激反应。
结论：
Rac 1通过NADPH氧化酶激活诱导糖尿病小鼠心肌重塑和功能障碍。Rac 1信号转导可能与ER应激和炎症有关。因此，靶向抑制Rac 1和NADPH氧化酶可能成为治疗糖尿病心肌病的一种新方法。
使用试剂原文信息：Tissue sections (5 μm) were stained with antibodies against tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-α1, and GRP78, respectively. Detection was carried out by using the EnVision+ system and diaminobenzidine (USCNLIFE, China) as described previously (20).