Tempol ameliorates cardiac fibrosis in streptozotocin-induced diabetic rats: role of oxidative stress in diabetic cardiomyopathy
Tempol ameliorates cardiac fibrosis in streptozotocin-induced diabetic rats: role of oxidative stress in diabetic cardiomyopathy
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DOI：
10.1007/s00210-013-0904-x
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发表时间：
2013-12-01
影响因子：
3.6
通讯作者：
Mohafez, Omar M. M.
中科院分区：
文献类型：
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作者：
Taye, Ashraf;Abouzied, Mekky M.;Mohafez, Omar M. M.
长期存在的糖尿病与氧化应激和心脏纤维化增加有关。这反过来又有助于心肌病的进展。本研究旨在探讨自由基清除剂4-羟基-2，2，6，6-四甲基哌啶（tempol）对糖尿病心肌病的保护作用及其机制。通过单次腹腔注射剂量的链脲佐菌素（50 mg/kg）在大鼠中诱导糖尿病。这些动物用tempol（18 mg/kg/天，口服）治疗8周。我们的研究结果显示，与对照组相比，糖尿病大鼠心脏组织中IV型胶原蛋白和纤连蛋白水平显著增加，明胶-凝胶酶谱法测定的基质金属蛋白酶-2（MMP-2）活性显著降低，ELISA或免疫组化法测定的心脏转化生长因子（TGF）-β水平升高。与对照组相比，这伴随着氧化应激的增加，表现为活性氧（ROS）产生增加和抗氧化酶能力降低沿着乳酸脱氢酶（LDH）和肌酸激酶（CK-MB）血清水平升高。Tempol治疗显著纠正了心脏细胞外基质、TGF-β、ROS或血清LDH、CK-MB水平的变化，并使MMP-2活性沿着正常化，同时保护了糖尿病大鼠心脏组织的完整性，使其免受损伤反应。此外，tempol使糖尿病大鼠升高的收缩压正常化，并改善某些心脏功能。总的来说，我们的数据表明，tempol通过减少氧化应激和细胞外基质重塑对糖尿病相关的大鼠心脏纤维化具有潜在的保护作用。
Long-standing diabetes is associated with increased oxidative stress and cardiac fibrosis. This, in turn, contributes to the progression of cardiomyopathy. The present study was sought to investigate whether the free radical scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) can protect against diabetic cardiomyopathy and to explore the specific underlying mechanism(s) in this setting. Diabetes was induced in rats by a single intraperitoneal injection dose of streptozotocin (50 mg/kg). These animals were treated with tempol (18 mg kg(-1) day(-1), orally) for 8 weeks. Our results showed significant increases in collagen IV and fibronectin protein levels and a marked decrease in matrix metalloproteinase-2 (MMP-2) activity measured by gelatin-gel zymography alongside elevated cardiac transforming growth factor (TGF)-beta level determined using ELISA or immunohistochemistry in cardiac tissues of diabetic rats compared with control. This was accompanied by an increased in the oxidative stress as evidenced by increased reactive oxygen species (ROS) production and decreased antioxidant enzyme capacity along with elevated lactate dehydrogenase (LDH) and creatine kinase (CK-MB) serum levels as compared with the control. Tempol treatment significantly corrected the changes in the cardiac extracellular matrix, TGF-beta, ROS or serum LDH, CK-MB levels, and normalized MMP-2 activity along with preservation of cardiac tissues integrity of diabetic rats against damaging responses. Moreover, tempol normalized the elevated systolic blood pressure and improved some cardiac functions in diabetic rats. Collectively, our data suggest a potential protective role of tempol against diabetes-associated cardiac fibrosis in rats via reducing oxidative stress and extracellular matrix remodeling.