抑制 NADPH 氧化酶可减轻实验性糖尿病引起的心肌收缩功能障碍。
Inhibition of NADPH oxidase alleviates experimental diabetes-induced myocardial contractile dysfunction.
机构信息
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, USA.
出版信息
Diabetes Obes Metab. 2011 May;13(5):465-73. doi: 10.1111/j.1463-1326.2011.01369.x. Epub 2011 Jan 27.
AIM
O(2) (-) production is implicated in cardiac dysfunction for a number of diseases including diabetes. Activation of the O(2) (-)-producing enzyme NADPH oxidase is seen in diabetes, although its role in diabetic cardiomyopathy is unclear. This study was designed to evaluate the effect of NADPH oxidase inhibition on cardiac function in diabetes.
METHODS
Experimental diabetes was induced in adult C57 mice using streptozotocin (STZ, 150 mg/kg, i.p.) prior to the administration of the NADPH oxidase inhibitor apocynin (4 mg/kg/day) for 2 weeks. Left ventricular (LV) and myocyte contractile functions were evaluated using echocardiography and edge-detection, respectively.
RESULTS
STZ elicited hyperglycaemia and reduced body weight gain, which was unaffected by apocynin. STZ significantly reduced fractional shortening, LV wall thickness, peak shortening, maximal velocity and duration of shortening or relengthening, the effects of which - with the exception of wall thickness - were significantly attenuated or ablated by apocynin. Western blot analysis revealed that the effects of comparable Akt phosphorylation, reduced AMPK phosphorylation, downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase and lessened phosphorylation of phospholamban in diabetic myocardium were unaffected by apocynin. Both apocynin and the nitric oxide synthase (NOS) inhibitor l-arginine methyl ester (L-NAME) inhibited elevated O(2) (-) production in diabetes without any additive effect between the two, indicating the presence of endothelial nitric oxide synthase (eNOS) uncoupling. However, neither diabetes nor apocynin altered the expression of heat shock protein 90 and eNOS phosphorylation (Ser(1177)). In addition, apocynin mitigated elevated levels of nitrotyrosine and nitric oxide in diabetes.
CONCLUSION
Taken together, these data indicate the beneficial role of NADPH oxidase inhibition in diabetes-induced myocardial contractile dysfunction.
目的
O(2) (-) 的产生与包括糖尿病在内的许多疾病的心脏功能障碍有关。在糖尿病中观察到产生 O(2) (-) 的酶 NADPH 氧化酶的激活，尽管其在糖尿病性心肌病中的作用尚不清楚。本研究旨在评估 NADPH 氧化酶抑制对糖尿病心脏功能的影响。
方法
在给予 NADPH 氧化酶抑制剂 apocynin（4mg/kg/天）之前，使用链脲佐菌素（STZ，150mg/kg，腹腔内注射）诱导成年 C57 小鼠发生实验性糖尿病 2 周。使用超声心动图和边缘检测分别评估左心室（LV）和心肌收缩功能。
结果
STZ 引起高血糖和体重减轻，apocynin 对此无影响。STZ 显著降低了分数缩短、LV 壁厚度、峰值缩短、最大速度和缩短或再缩短的持续时间，除壁厚度外，这些效应均被 apocynin 显著减弱或消除。Western blot 分析显示，在糖尿病心肌中，可比较的 Akt 磷酸化、AMPK 磷酸化减少、肌浆网 Ca(2+)-ATP 酶下调和磷酸化减少对肌球蛋白轻链的作用不受 apocynin 影响。apocynin 和一氧化氮合酶（NOS）抑制剂 l-精氨酸甲酯（L-NAME）抑制糖尿病中升高的 O(2) (-) 产生，但两者之间没有相加作用，表明内皮型一氧化氮合酶（eNOS）解偶联。然而，糖尿病或 apocynin 均未改变热休克蛋白 90 和 eNOS 磷酸化（Ser(1177)）的表达。此外，apocynin 减轻了糖尿病中升高的硝基酪氨酸和一氧化氮水平。
结论
综上所述，这些数据表明 NADPH 氧化酶抑制在糖尿病引起的心肌收缩功能障碍中具有有益作用。
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