The AGE-breaker ALT-711 restores high blood flow-dependent remodeling in mesenteric resistance arteries in a rat model of type 2 diabetes.
The AGE-breaker ALT-711 restores high blood flow-dependent remodeling in mesenteric resistance arteries in a rat model of type 2 diabetes.
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作者：
Freidja ML;Tarhouni K;Toutain B;Fassot C;Loufrani L;Henrion D
血流介导的阻力动脉重塑对于缺血性疾病的血运重建是必不可少的，但在糖尿病中这一点受到损害。我们假设，与瘦型Zucker(LZ)大鼠相比，切断晚期糖基化终末产物(AGE)交联链可以改善Zucker糖尿病肥胖(ZDF)大鼠肠系膜阻力动脉的重塑。在体内交替结扎动脉后，暴露于高血流(HF)或正常血流(NF)的动脉，2周后收集动脉。在LZ大鼠，HF动脉直径大于NF血管，而在ZDF大鼠则不是这样。与LZ大鼠相比，ZDF大鼠HF动脉内皮细胞介导的扩张性进一步降低。用年龄断裂剂4，5-二甲基-3-苯基四氮唑氯化铵(ALT-711)(3 mg/kg/天，3周)治疗大鼠可逆转糖尿病引起的心衰依赖的重塑损伤。ALT-711还改善肠系膜阻力动脉内皮一氧化氮依赖的松弛。活性氧减少可使ZDF大鼠的松弛功能恢复，但对LZ或ALT-711处理的大鼠则不能。与ZDF大鼠相比，ALT-711治疗的ZDF大鼠的AGE降低。与LZ大鼠相比，ZDF大鼠心力衰竭依赖重塑所必需的金属蛋白酶活性降低，并经ALT-711恢复。因此，靶向AGE的交叉链接可能为克服糖尿病中发生的缺血性疾病的微血管并发症提供治疗潜力。
Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases, but this is impaired in diabetes. We hypothesized that breaking advanced glycation end product (AGE) cross-links could improve remodeling in mesenteric resistance arteries in Zucker diabetic fatty (ZDF) rats compared with lean Zucker (LZ) rats. Arteries, exposed to high (HF) or normal (NF) blood flow after alternate arterial ligation in vivo, were collected after 2 weeks. In LZ rats, HF artery diameter was larger than for NF vessels, but this was not the case in ZDF rats. Endothelium-mediated dilation in ZDF rats, which was lower than in LZ rats, was further decreased in HF arteries. Treatment of rats with the AGE-breaker 4,5-dimethyl-3-phenacylthiazolium chloride (ALT-711) (3 mg/kg/day; 3 weeks) reversed diabetes-induced impairment of HF-dependent remodeling. ALT-711 also improved endothelium nitric oxide–dependent relaxation in mesenteric resistance arteries. Reactive oxygen species reduction restored relaxation in ZDF rats but not in LZ or ALT-711–treated rats. AGEs were reduced in ALT-711–treated ZDF rats compared with ZDF rats. Metalloproteinase activity, necessary for HF-dependent remodeling, was reduced in ZDF rats compared with LZ rats and restored by ALT-711. Thus, targeting AGE cross-links may provide a therapeutic potential for overcoming microvascular complications in ischemic disorders occurring in diabetes.
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影响因子：
8.2
作者：
Brouwers, O.;Niessen, P. M.;Haenen, G.;Miyata, T.;Brownlee, M.;Stehouwer, C. D.;De Mey, J. G.;Schalkwijk, C. G.
通讯作者：
Schalkwijk, C. G.
影响因子：
15.9
作者：
Rumble, JR;Cooper, ME;Gilbert, RE
通讯作者：
Gilbert, RE
影响因子：
8.3
作者：
Bouvet, Celine;de Chantemele, Eric Belin;Henrion, Daniel
通讯作者：
Henrion, Daniel
影响因子：
8.3
作者：
Endemann, DH;Pu, Q;Schiffrin, EL
通讯作者：
Schiffrin, EL
影响因子：
20.1
作者：
Loufrani, L;Levy, BI;Henrion, D
通讯作者：
Henrion, D