The First Hospital of Jilin University, Changchun, China; Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, Kentucky;
The First Hospital of Jilin University, Changchun, China;
Am J Physiol Endocrinol Metab. 2014 Jun 1;306(11):E1239-47. doi: 10.1152/ajpendo.00629.2013. Epub 2014 Apr 8.
The development of diabetic cardiomyopathy is attributed to diabetic oxidative stress, which may be related to the mitogen-activated protein kinase (MAPK) c-Jun NH2-terminal kinase (JNK) activation. The present study tested a hypothesis whether the curcumin analog C66 [(2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene) cyclohexanone] as a potent antioxidant can protect diabetes-induced cardiac functional and pathogenic changes via inhibition of JNK function. Diabetes was induced with a single intraperitoneal injection of streptozotocin in male C57BL/6 mice. Diabetic and age-matched control mice were randomly divided into three groups, each group treated with C66, JNK inhibitor (JNKi, SP600125), or vehicle (1% CMC-Na solution) by gavage at 5 mg/kg every other day for 3 mo. Neither C66 nor JNKi impacted diabetic hyperglycemia and inhibition of body-weight gain, but both significantly prevented diabetes-induced JNK phosphorylation in the heart. Compared with basal line, cardiac function was significantly decreased in diabetic mice at 3 mo of diabetes but not in C66- or JNKi-treated diabetic mice. Cardiac fibrosis, oxidative damage, endoplasmic reticulum stress, and cell apoptosis, examined by Sirius red staining, Western blot, and thiobarbituric acid assay, were also significantly increased in diabetic mice, all which were prevented by C66 or JNKi treatment under diabetic conditions. Cardiac metallothionein expression was significantly decreased in diabetic mice but was almost normal in C66- or JNKi-treated diabetic mice. These results suggest that, like JNKi, C66 is able to prevent diabetic upregulation of JNK function, resulting in a prevention of diabetes-induced cardiac fibrosis, oxidative stress, endoplasmic reticulum stress, and cell death, along with a preservation of cardiac metallothionein expression.
糖尿病心肌病的发展归因于糖尿病氧化应激，这可能与有丝分裂原激活蛋白激酶（MAPK）c-Jun NH2-末端激酶（JNK）的激活有关。本研究通过抑制 JNK 功能，检验姜黄素类似物 C66[（2E，6E）-2,6-双（2-（三氟甲基）苄叉）环己酮]作为一种有效的抗氧化剂，是否可以保护糖尿病引起的心脏功能和病变改变的假说。雄性 C57BL/6 小鼠经单次腹腔注射链脲佐菌素诱导糖尿病。糖尿病和年龄匹配的对照组小鼠随机分为三组，每组用 C66、JNK 抑制剂（JNKi，SP600125）或载体（1%CMC-Na 溶液）灌胃，每两天一次，持续 3 个月。C66 和 JNKi 均不影响糖尿病的高血糖和体重增加抑制，但均显著阻止糖尿病诱导的心脏 JNK 磷酸化。与基线相比，糖尿病 3 个月时，糖尿病小鼠的心脏功能明显下降，但 C66 或 JNKi 治疗的糖尿病小鼠的心脏功能没有下降。用天狼猩红染色、Western blot 和硫代巴比妥酸法检测到心脏纤维化、氧化损伤、内质网应激和细胞凋亡也显著增加，在糖尿病条件下，C66 或 JNKi 治疗均可预防这些变化。糖尿病小鼠心脏金属硫蛋白表达明显降低，但 C66 或 JNKi 治疗的糖尿病小鼠几乎正常。这些结果表明，与 JNKi 一样，C66 能够防止糖尿病 JNK 功能上调，从而预防糖尿病引起的心脏纤维化、氧化应激、内质网应激和细胞死亡，并保留心脏金属硫蛋白的表达。
