Deficiency of rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes.
Deficiency of rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes.
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作者：
Li J;Zhu H;Shen E;Wan L;Arnold JM;Peng T
我们最近的研究表明，Rac1和NADPH氧化酶的激活有助于短期糖尿病的心肌细胞凋亡。本研究旨在探讨破坏Rac1和抑制NADPH氧化酶是否能预防慢性糖尿病患者的心肌重构。用链脲佐菌素注射心肌细胞特异性敲除Rac1小鼠及其野生型仔鼠，诱导其发生糖尿病。在另一项单独的实验中，野生型糖尿病小鼠分别用饮水中的载药或夹竹桃素治疗。糖尿病患者2个月后观察心肌肥大、纤维化、内质网应激、炎症反应和心肌功能。培养分离的成年大鼠心肌细胞，并用高糖刺激。在糖尿病心脏中，NADPH氧化酶的激活、亚基的表达和活性氧的产生被Rac1敲除或罗布麻素处理抑制。糖尿病小鼠心肌胶原沉积和心肌细胞横截面积显著增加，并伴有促纤维化基因和增生性基因的表达升高。缺乏Rac1或罗布麻素可减少心肌纤维化和肥厚，从而改善心肌功能。这些影响与糖尿病心脏内质网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，高糖诱导的内质网应激可通过阻断Rac1或NADPH氧化酶来抑制。Rac1通过激活NADPH氧化酶诱导糖尿病小鼠心肌重构和功能障碍。Rac1信号的作用可能与内质网应激和炎症有关。因此，靶向抑制Rac1和NADPH氧化酶可能是治疗糖尿病性心肌病的一种方法。
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. 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. 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. 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.
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