Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy

Oxygen-induced retinopathy (OIR) in the mouse, like the analogous human disease retinopathy of prematurity, is an ischemic retinopathy dependent on oxygen-induced vascular obliteration. We tested the hypothesis that chemically overriding the oxygen-induced downregulation of hypoxia-inducible factor (HIF) activity would prevent vascular obliteration and subsequent pathologic neovascularization in the OIR model. Because the degradation of HIF-1α is regulated by prolyl hydroxylases, we examined the effect of systemic administration of a prolyl hydroxylase inhibitor, dimethyloxalylglycine, in the OIR model. Our results determine that stabilizing HIF activity in the early phase of OIR prevents the oxygen-induced central vessel loss and subsequent vascular tortuosity and tufting that is characteristic of OIR. Overall, these findings imply that simulating hypoxia chemically by stabilizing HIF activity during the causative ischemia phase (hyperoxia) of retinopathy of prematurity may be of therapeutic value in preventing progression to the proliferative stage of the disease.     

Neuroprotection by dimethyloxalylglycine following permanent and transient focal cerebral ischemia in rats

Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain (PHD) enzymes that regulate the stability of hypoxia-inducible factor (HIF). We investigated the effect of DMOG on the outcome after permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Before and after pMCAO, rats were treated with 40 mg/kg, 200 mg/kg DMOG, or vehicle, and with 40 mg/kg or vehicle after tMCAO. Serial magnetic resonance imaging (MRI) was performed to assess infarct evolution and regional cerebral blood flow (rCBF). Both doses significantly reduced infarct volumes, but only 40 mg/kg improved the behavior after 24 hours of pMCAO. Animals receiving 40 mg/kg were more likely to maintain rCBF values above 30% from the contralateral hemisphere within 24 hours of pMCAO. DMOG after tMCAO significantly reduced the infarct volumes and improved behavior at 24 hours and 8 days and also improved the rCBF after 24 hours. A consistent and significant upregulation of both mRNA and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was associated with the observed neuroprotection, although this was not consistently related to HIF-1α levels at 24 hours and 8 days. Thus, DMOG afforded neuroprotection both at 24 hours after pMCAO and at 24 hours and 8 days after tMCAO. This effect was associated with an increase of VEGF and eNOS and was mediated by improved rCBF after DMOG treatment.     

Stabilization of hypoxia-inducible factor ameliorates glomerular injury sensitization after tubulointerstitial injury

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二甲基乙二酰基甘氨酸对跨区穿支皮瓣Choke Ⅱ区血管生成的影响机制研究

目的研究二甲基乙二酰基甘氨酸(dimethyloxalylglycine,DMOG)对跨区穿支皮瓣Choke Ⅱ区血管生成的影响及作用机制。方法将126只成年雄性SD大鼠随机分为DMOG组、YC-1组和空白对照组,每组42只。3组大鼠背部制作大小为12 cm×3 cm的跨区穿支皮瓣模型;于术前1 d、2 h及术后1、2、3 d分别腹腔注射DMOG(40 mg/kg)、YC-1(HIF-1α抑制剂,10 mg/kg)和等量生理盐水。术后观察各组大鼠皮瓣成活情况,7 d时测量皮瓣成活面积并计算皮瓣成活率,皮瓣透光实验、明胶-氧化铅血管造影及HE染色观察皮瓣Choke Ⅱ区血管生成情况,免疫组织化学染色及Western blot法检测皮瓣Choke Ⅱ区VEGF及HIF-1α表达;3、5、7 d ELISA法测定皮瓣Choke Ⅱ区VEGF和HIF-1α蛋白含量。结果术后7 d时DMOG组皮瓣远端未见明显坏死,空白对照组和YC-1组皮瓣均发生坏死且主要位于远端;DMOG组皮瓣成活率为90.28%±1.37%,高于YC-1组84.28%±1.45%及空白对照组85.83%±1.60%,差异有统计学意义(P<0.05)。DMOG组皮瓣Choke Ⅱ区血管较多且结构清晰、完整;YC-1组、空白对照组中Choke Ⅱ区血管较少且结构紊乱。DMOG组血管数量为(25.56±1.29)条/视野,高于YC-1组(7.38±0.54)条/视野及空白对照组(14.48±0.91)条/视野,差异有统计学意义(P<0.05)。术后3、5、7 d,DMOG组皮瓣Choke Ⅱ区HIF-1α、VEGF表达均高于其余两组,差异有统计学意义(P<0.05)。结论 DMOG能促进跨区穿支皮瓣Choke Ⅱ区血管生成,加速皮瓣早期血管化进程,改善微循环和血供,降低皮瓣缺血、缺氧损伤程度,提高成活率。