Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, China.
Acta Pharmacol Sin. 2011 Aug;32(8):999-1008. doi: 10.1038/aps.2011.54. Epub 2011 Jul 11.
To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts.
A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rho-kinase inhibitor fasudil hydrochloride hydrate (10 mg·kg(-1)·d(-1), ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting.
In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved.
The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.
研究 RhoA/Rho 激酶（ROCK）的激活是否与糖尿病心脏中的心肌纤维化有关。
使用高脂肪饮食联合链脲佐菌素（30mg/kg，ip）建立 2 型糖尿病大鼠模型。动物随机分为 3 组：对照组大鼠、未治疗的糖尿病大鼠给予载体和治疗的糖尿病大鼠给予 Rho 激酶抑制剂盐酸法舒地尔（10mg·kg(-1)·d(-1)，ip，持续 14 周）。体内评估心脏收缩功能。使用免疫组织化学和 TEM 观察心脏纤维化的形态特征。使用 RT-PCR 评估 JNK、TGFβ1、I 型和 III 型前胶原的 mRNA 表达。使用 Western blot 评估 MYPT1、JNK 和 Smad2/3 的磷酸化以及 TGFβ1 和 c-Jun 的蛋白水平。
与对照组大鼠相比，未治疗的糖尿病大鼠出现心肌纤维化，心脏收缩功能明显降低。在未治疗的糖尿病大鼠心脏中，JNK 的 mRNA 表达水平和活性上调；TGFβ1 的表达和 Smad2/3 的磷酸化增加。在治疗的糖尿病大鼠心脏中，JNK 和 TGFβ/Smad 的激活明显降低，心肌纤维化减少，心脏收缩功能改善。
数据表明盐酸法舒地尔可改善 2 型糖尿病大鼠的心肌纤维化，至少部分通过抑制 JNK 和 TGFβ/Smad 途径。抑制 RhoA/ROCK 可能是预防糖尿病心肌病的新治疗靶点。
