Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, 61511, Minya, Egypt,
Naunyn Schmiedebergs Arch Pharmacol. 2013 Dec;386(12):1071-80. doi: 10.1007/s00210-013-0904-x. Epub 2013 Aug 16.
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)-β 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-β, 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.
长期的糖尿病与氧化应激和心脏纤维化增加有关。这反过来又导致心肌病的进展。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氧自由基（tempol）是否可以预防糖尿病性心肌病，并探讨在这种情况下的具体潜在机制。糖尿病通过单次腹腔注射链脲佐菌素（50mg/kg）诱导大鼠。这些动物用 tempol（18mgkg(-1)天(-1)，口服）治疗 8 周。我们的结果表明，糖尿病大鼠心脏组织中的胶原 IV 和纤维连接蛋白蛋白水平显著升高，明胶凝胶电泳测定的基质金属蛋白酶-2（MMP-2）活性显著降低，ELISA 或免疫组织化学测定的心脏转化生长因子（TGF）-β水平升高。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，同时乳酸脱氢酶（LDH）和肌酸激酶同工酶（CK-MB）血清水平升高。与对照组相比，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，并使糖尿病大鼠的 MMP-2 活性正常化，同时保持心脏组织的完整性，防止对损伤的反应。此外，Tempol 还可使糖尿病大鼠的收缩压升高和部分心脏功能得到改善。总之，我们的数据表明，Tempol 通过减少氧化应激和细胞外基质重塑，对大鼠糖尿病相关的心脏纤维化具有潜在的保护作用。
