N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition.
N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition.
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N-乙酰半胱氨酸改善糖尿病心脏功能：抑制纤维化的可能作用
DOI：
10.1186/s12872-015-0076-3
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发表时间：
2015-08-06
影响因子：
2.1
通讯作者：
Yuan LJ
中科院分区：
文献类型：
--
作者：
Liu C;Lu XZ;Shen MZ;Xing CY;Ma J;Duan YY;Yuan LJ
糖尿病心肌病是糖尿病（DM）患者的主要死因之一。本研究旨在探究N - 乙酰 - L - 半胱氨酸（NAC，一种抗氧化剂及谷胱甘肽前体）的治疗意义及可能的潜在机制。
研究纳入了35只12周龄的雄性C57BL/6小鼠。25只糖尿病小鼠通过腹腔注射溶解于柠檬酸盐缓冲液中的链脲佐菌素（STZ，150 mg/kg，Sigma - Aldrich）诱导产生，注射前小鼠需禁食过夜。血糖水平高于13.5 mmol/L的小鼠被视为糖尿病小鼠。作为非糖尿病（糖尿病）对照组，小鼠注射等量的柠檬酸盐缓冲液。25只糖尿病小鼠分为5组，每组5只：包括DM组（未接受NAC治疗的糖尿病组），以及4个不同的NAC治疗组，即NAC1、NAC3、NAC5和NAC7组，数字代表NAC治疗的起始时间点。在10只非糖尿病小鼠中，部分小鼠不接受治疗（Ctrl组），部分接受NAC治疗5周（仅NAC组）。STZ注射12周后进行超声心动图检查。超声心动图检查后收集心脏组织，进行苏木精 - 伊红（HE）染色、三色染色及活性氧（ROS）染色。分离、培养心脏成纤维细胞，并用高糖加NAC或赋形剂处理。进行定量聚合酶链反应（qPCR）分析及CCK - 8检测，以观察纤维化基因表达及细胞增殖情况。
我们发现，STZ诱导12周后，心脏收缩功能和舒张功能均受损，同时伴有过量的氧化应激反应及心脏纤维化。NAC显著减少了ROS生成和纤维化，同时改善了心脏收缩功能和舒张功能。值得注意的是，NAC1组治疗时间更早且更长，心脏功能得到显著改善，纤维化程度更低。在心脏成纤维细胞中，NAC阻断了高血糖诱导的心脏成纤维细胞增殖及胶原蛋白合成。
我们的研究表明，糖尿病中使用NAC治疗可有效预防糖尿病心肌病，可能是通过抑制ROS生成和纤维化实现的，这一点有待进一步阐明。
本文的网络版本（doi:10.1186/s12872 - 015 - 0076 - 3）包含补充材料，仅供授权用户使用。
BackgroundDiabetic cardiomyopathy is one of the leading causes of death in diabetes mellitus (DM) patients. This study aimed to explore the therapeutic implication of N-acetyl-L-cysteine (NAC, an antioxidant and glutathione precursor) and the possible underlying mechanism.MethodsThirty five 12-week-old male C57BL/6 mice were included. Twenty-five diabetic mice were induced by intraperitoneal injection of streptozocin (STZ, 150 mg/kg, Sigma-Aldrich) dissolved in a mix of citrate buffer after overnight fast. Mice with a blood glucose level above 13.5 mmol/L were considered diabetic. As a non-DM (diabetic) control, mice were injected with equal volume of citrate buffer. The 25 diabetic mice were divided into 5 groups with 5 animals in each group: including DM (diabetes without NAC treatment), and 4 different NAC treatment groups, namely NAC1, NAC3, NAC5 and NAC7, with the number defining the start time point of NAC treatment. In the 10 non-DM mice, mice were either untreated (Ctrl) or treated with NAC for 5 weeks (NAC only). Echocardiography was performed 12 weeks after STZ injection. Heart tissue were collected after echocardiography for Hematoxylin Eosin (HE) and Trichrome staining and ROS staining. Cardiac fibroblast cells were isolated, cultured and treated with high glucose plus NAC or the vehicle. qPCR analysis and CCK-8 assay were performed to observe fibrotic gene expression and cell proliferation.ResultsWe found that both cardiac systolic function and diastolic function were impaired, coupled with excessive reactive oxygen stress and cardiac fibrosis 12 weeks after STZ induction. NAC significantly reduced ROS generation and fibrosis, together with improved cardiac systolic function and diastolic function. Strikingly, NAC1 treatment, which had the earlier and longer treatment, produced significant improvement of cardiac function and less fibrosis. In the cardiac fibroblasts, NAC blocked cardiac fibroblast proliferation and collagen synthesis induced by hyperglycemia.ConclusionsOur study indicates that NAC treatment in diabetes effectively protects from diabetic cardiomyopathy, possibly through inhibiting the ROS production and fibrosis, which warrants further clarification.