[1]季中华,曾路路,陈永军,等.MRL-45696 减轻2 型糖尿病大鼠心肌缺血再灌注后的DNA损伤[J].南方医科大学学报,2018,(07):830.
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MRL-45696 减轻2 型糖尿病大鼠心肌缺血再灌注后的DNA损伤()
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《南方医科大学学报》[ISSN:1673-4254/CN:44-1627/R]

卷:
期数:
2018年07期
页码:
830
栏目:
出版日期:
2018-06-30

文章信息/Info

Title:
Poly(ADP-ribose) polymerases-1 inhibitor MRL-45696 alleviates DNA damage after myocardial ischemia-reperfusion in diabetic rats
作者:
季中华曾路路陈永军梁根强
关键词:
二磷酸腺苷核糖聚合酶抑制剂MRL-45696糖尿病模型缺血再灌注损伤模型DNA损伤
Keywords:
poly(ADP-ribose) polymerase-1 MRL-45696 diabetic model ischemia-reperfusion injury DNAdamage
摘要:
目的研究摄食二磷酸腺苷核糖聚合酶抑制剂MRL-45696是否减轻2型糖尿病大鼠心肌缺血/再灌注后DNA的损伤。方 法大鼠高糖高脂饲料喂食8 周后腹腔注射链脲佐菌素(STZ)(30 mg/kg),构建2型糖尿病大鼠模型,选取2型糖尿病大鼠40 只,随机分为糖尿病组(DM)、假手术组(S)、MRL-45696治疗+假手术组(NO)、缺血再灌注损伤模型组(MI/R)、MRL-45696治 疗+缺血再灌注损伤组(MRL),每组各8只。灌胃给予2型糖尿病大鼠MRL-45696 (50 mg/kg·d),1周后以大鼠冠状动脉左前降 支结扎30 min 再灌注120 min 的方法制作心肌缺血再灌注损伤模型。检测大鼠血浆心肌肌钙蛋白Ⅰ(cTnI)、血清肌酸激酶 (CK)、血清乳酸脱氢酶(LDH)活性和心肌梗死范围、细胞凋亡比例、丙二醛(MDA)、超氧化物歧化酶活性(SOD)。Western blot 检测γ-H2AX、cleaved caspase-3、PARP-1、PAR;比色法检测大鼠心肌组织中烟酰胺腺嘌呤二核苷酸(NAD)水平(以NAD+/ NADH比例代表)。结果MRL组心肌梗死面积显著小于MI/R 组(P<0.05),MI/R 组cTnI、CK、LDH、MDA、γ-H2AX、cleaved caspase-3表达水平及细胞凋亡较其它组显著升高(P<0.05),而SOD水平明显降低(P<0.05);与MI/R组相比,MRL组大鼠cTnI、 CK、LDH、MDA、γ-H2AX、cleaved caspase-3、PARP-1、PAR表达水平及细胞凋亡明显降低,SOD及NAD表达水平明显升高,差 异有统计学意义(P<0.05)。结论糖尿病加重大鼠心肌细胞缺血再灌注后DNA损伤,MRL-45696 可能通过抑制糖尿病大鼠 PARP-1的过度激活,减轻心肌细胞缺血再灌注损伤,减少心肌梗死面积。
Abstract:
Objective To study the protective effect of MRL-45696, an inhibitor of poly(ADP- ribose) polymerase-1 (PARP-1), against DNA damage after myocardial ischemia/reperfusion (I/R) in diabetic rats. Methods Rat models of type 2 diabetes mellitus were established by high-fat feeding and a single peritoneal dose of streptozotocin. Forty diabetic rats were randomized equally into diabetic group, sham-operated group, sham-operated group with MRL-45696 treatment, I/R injury model group and I/R injury group with MRL-45696 treatment. The rats in MRL-45696-treated groups were subjected to daily intragastric administration of MRL-45696 (50 mg/kg) for 7 consecutive days, after which sham operation was performed or myocardial I/R injury was induced by ligation of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. The range of myocardial infarction, plasma cardiac troponin I (cTnI), serum creatine kinase (CK), lactate dehydrogenase (LDH) activity, malondialdehyde (MDA), superoxide dismutase (SOD) activity, and cardiac myocyte apoptosis were detected. The levels of γ-H2AX, cleaved caspase-3, PARP-1, and PAR were detected with Western blotting, and the level of NAD was detected using colorimetry. Results The infarct size was significantly smaller in MRL-45696 treatment group than in I/R injury group (P<0.05). In I/R model group, the levels of cTnI, CK, and LDH in the plasma or serum and MDA, γ-H2AX, cleaved caspase-3 and apoptotic rate in the cardiac myocytes were significantly higher than those in the other groups (P<0.05), and SOD activity was significantly decreased (P<0.05). Compared with I/R model group, the rats with MRL- 45696 treatment showed significantly decreased levels of cTnI, CK, LDH, MDA, γ-H2AX, cleaved caspase-3, PARP- 1, PAR expression and cell apoptosis with significantly increased levels of SOD and NAD (P<0.05). Conclusion MRL-45696 can inhibit excessive activation of PARP-1, increase intracellular level of NAD and inhibit cardiac myocyte apoptosis to alleviate myocardial I/R-induced DNAdamage and reduce myocardial infarct size in diabetic rats.
更新日期/Last Update: 1900-01-01