硫氢化钠对糖尿病心肌病大鼠心脏保护作用及对JNK/FoxO1/Bcl-2信号通路的影响

摘要： 目的 观察外源性硫化氢的供体硫氢化钠 （NaHS） 对糖尿病心肌病 （DCM） 大鼠模型心肌损伤的保护作用及相关机制。方法 运用糖尿病饮食及链脲佐菌素 （STZ） 腹腔注射法建立DCM大鼠模型； 选取DCM大鼠16只， 正常大鼠16只， 随机分为DCM+0.9%氯化钠组 （DCM+Saline组）、 DCM+硫氢化钠组 （DCM+NaHS组）、 正常大鼠+0.9%氯化钠组 （Control+Saline组）、 正常大鼠+硫氢化钠组 （Control+NaHS组）， 每组8只； 予以DCM+NaHS组、 Control+NaHS组腹腔注射NaHS溶液100 mmol/ （kg·d）（浓度12 mmol/L， 体积8.3 mL/kg）， DCM+Saline组、 Control+Saline组大鼠腹腔注射等量生理盐水， 持续12周。实验结束行心脏超声测定左室射血分数 （LVEF） 及左室缩短分数 （LVFS）， 随后取左室心肌组织， 采用HE染色及Masson染色观察心肌组织病理改变， Western blot实验检测B淋巴细胞瘤-2基因 （Bcl-2）、磷酸化氨基末端蛋白激酶 （p-JNK）、 磷酸化叉头蛋白家族1 （p-FoxO1） 蛋白的表达。结果 糖尿病及硫氢化钠对大鼠心功能指标、 p-JNK、 p-FoxO1及Bcl-2蛋白有影响， 除外Bcl-2蛋白均存在交互作用 （P＜0.05）； 其中， DCM大鼠 LVEF及LVFS下降、 心肌细胞肥大及心肌间质纤维化， Bcl-2、 p-FoxO1蛋白表达下降、 p-JNK蛋白表达增加 （P＜ 0.05）； NaHS可以使DCM大鼠心功能指标、 病理组织变化得到改善， Bcl-2、 p-FoxO1蛋白表达增加、 p-JNK蛋白表达减少 （P＜0.05）。结论 DCM心肌损伤与细胞凋亡相关， 硫氢化钠可以减轻DCM心肌损伤保护心脏功能， 可能通过作用于JNK/FoxO1/Bcl-2发挥作用。

Exogenous H2S protects against diabetic cardiomyopathy and might act on JNK/FoxO1/Bcl-2 pathway

Abstract: Objective To investigate the protective effects and the related mechanism of exogenous H2S on diabetic cardiomyopathy (DCM) in rats. Methods Intraperitoneal injection of streptozotocin and diabetic diet were used in healthy male Sprague-Dawley rats were used to establish DCM models. Sixteen DCM rats and 16 normal rats were randomly divided into the following four groups with 8 rats per group: DCM+ saline group, DCM+NaHS group, Control + saline group and Control+NaHS group. DCM+NaHS group rats and Control+NaHS group rats were intraperitoneally administered H2S donor sodium hydrosulfide (NaHS) at a dose of 100 μmol/kg per day for 12 weeks. DCM+saline group rats and Control+saline group rats were intraperitoneally injected with an equivalent volume of physiological saline for 12 weeks. At the end of the experiment, all rats were tested with ultrasonic cardiogram to evaluate the heart function. Then, the left heart ventrucular tissues were collected after executing all rats to be embedded in paraffin and be preserved at - 80 ℃ . The cardiac pathological changes were observed by hematoxylin and eosin staining. The protein expressions of Bcl-2, p-FoxO1, p-JNK were detected by Western blot assay. Results The type of rat model and interving measure showed an effect on the cardiac function, as well as Bcl-2, p-FoxO1 and p-JNK; There was an interaction between the type of rat model and interving measure during the experiment. In DCM group, the levels of LVEF and LVFS values and expressions of Bcl-2 and p-FoxO1 were declined, but the expression of p-JNK was increased. The heart function and cardiac pathological changes were improved in NaHS group. Likewise, expressions of Bcl-2 and p-FoxO1 were upregulated, the expression of p-JNK was downregulated. Conclusion DCM myocardial injury is associated with cell apoptosis. NaHS can alleviate DCM myocardial injury and protect cardiac function, possibly by acting on JNK/FoxO1/Bcl-2 pathway.