Baker IDI Heart and Diabetes Institute, Melbourne 8008, VIC, Australia.
Free Radic Biol Med. 2013 Jul;60:307-17. doi: 10.1016/j.freeradbiomed.2013.02.021. Epub 2013 Feb 26.
Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left-ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated proinflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55mg/kg/day for 5 days), to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, the mice were allocated to coenzyme Q10 supplementation (10mg/kg/day), treatment with the angiotensin-converting-enzyme inhibitor (ACE-I) ramipril (3mg/kg/day), treatment with olive oil vehicle, or no treatment for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22(phox), p47(phox) and superoxide production), LV uncoupling protein UCP3 expression, and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q10. Coenzyme Q10 substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure, and LV -dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis), and LV expression of proinflammatory mediators (tumor necrosis factor-α, with a similar trend for interleukin IL-1β). Coenzyme Q10's actions were independent of glycemic control, body mass, and blood pressure. Coenzyme Q10 compared favorably to improvements observed with ramipril. In summary, these data suggest that coenzyme Q10 effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q10 supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients.
心脏氧化应激是与糖尿病心肌病相关的早期事件，由高血糖引发。我们检验了这样一个假设，即靶向治疗高血糖后左心室（LV）活性氧（ROS）的上调，可以减轻 1 型糖尿病引起的 LV 重构和功能障碍，同时减轻促炎标志物和心肌细胞凋亡。6 周龄雄性小鼠接受链脲佐菌素（55mg/kg/天，持续 5 天）治疗，以诱导 1 型糖尿病，或柠檬酸缓冲液载体。高血糖 4 周后，将小鼠分配至辅酶 Q10 补充（10mg/kg/天）、血管紧张素转换酶抑制剂（ACE-I）雷米普利（3mg/kg/天）治疗、橄榄油载体治疗或不治疗 8 周。1 型糖尿病上调 LV NADPH 氧化酶（Nox2、p22（phox）、p47（phox）和超氧化物产生）、LV 解偶联蛋白 UCP3 表达以及 LV 和全身氧化应激（LV 3-硝基酪氨酸和血浆脂质过氧化）。辅酶 Q10 显著减轻了所有这些。辅酶 Q10 极大地限制了 1 型糖尿病引起的 LV 舒张功能障碍（超声心动图的 E:A 比和减速时间、LV 舒张末期压力和 LV-dP/dt 的微测压法）、LV 重构（心肌细胞肥大、心脏纤维化、细胞凋亡）和 LV 促炎介质（肿瘤坏死因子-α，白细胞介素 IL-1β 也有类似趋势）的表达。辅酶 Q10 的作用独立于血糖控制、体重和血压。辅酶 Q10 的作用优于雷米普利观察到的改善。总之，这些数据表明，辅酶 Q10 可有效靶向 LV ROS 上调，以限制 1 型糖尿病性心肌病。因此，辅酶 Q10 补充可能是 1 型糖尿病患者心脏并发症治疗中替代 ACE-I 的有效方法。
