Department of Integrated Neurovascular and Mitochondrial Biology, University of Angers, Angers, France.
PLoS One. 2013 Jul 9;8(7):e68217. doi: 10.1371/journal.pone.0068217. Print 2013.
Endothelial dysfunction in resistance arteries alters end organ perfusion in type 2 diabetes. Superoxides and cyclooxygenase-2 (COX-2) derivatives have been shown separately to alter endothelium-mediated relaxation in aging and diabetes but their role in the alteration of vascular tone in old diabetic subjects is not clear, especially in resistance arteries. Consequently, we investigated the role of superoxide and COX-2-derivatives on endothelium-dependent relaxation in 3 and 12 month-old Zucker diabetic fatty (ZDF) and lean (LZ) rats. Mesenteric resistance arteries were isolated and vascular tone was investigated using wire-myography. Endothelium (acetylcholine)-dependent relaxation was lower in ZDF than in LZ rats (60 versus 84% maximal relaxation in young rats and 41 versus 69% in old rats). Blocking NO production with L-NAME was less efficient in old than in young rats. L-NAME had no effect in old ZDF rats although eNOS expression level in old ZDF rats was similar to that in old LZ rats. Superoxide level and NADPH-oxidase subunits (p67phox and gp91phox) expression level were greater in ZDF than in LZ rats and were further increased by aging in ZDF rats. In young ZDF rats reducing superoxide level with tempol restored acetylcholine-dependent relaxation to the level of LZ rats. In old ZDF rats tempol improved acetylcholine-dependent relaxation without increasing it to the level of LZ rats. COX-2 (immunolabelling and Western-blot) was present in arteries of ZDF rats and absent in LZ rats. In old ZDF rats arterial COX-2 level was higher than in young ZDF rats. COX-2 blockade with NS398 restored in part acetylcholine-dependent relaxation in arteries of old ZDF rats and the combination of tempol and NS398 fully restored relaxation in control (LZ rats) level. Accordingly, superoxide production and COX-2 derivatives together reduced endothelium-dependent relaxation in old ZDF rats whereas superoxides alone attenuated relaxation in young ZDF or old LZ rats.
在 2 型糖尿病中，阻力血管中的内皮功能障碍改变了终末器官的灌注。超氧化物和环氧化酶-2（COX-2）衍生物已分别显示可改变衰老和糖尿病中内皮介导的松弛，但它们在老年糖尿病患者血管张力改变中的作用尚不清楚，尤其是在阻力血管中。因此，我们研究了超氧化物和 COX-2 衍生物在 3 个月和 12 个月大的 Zucker 糖尿病肥胖（ZDF）和瘦（LZ）大鼠中的内皮依赖性松弛中的作用。分离肠系膜阻力血管并用线描记法研究血管张力。ZDF 大鼠的内皮依赖性松弛（乙酰胆碱）低于 LZ 大鼠（年轻大鼠中最大松弛度为 60%对 84%，老年大鼠中为 41%对 69%）。与年轻大鼠相比，老年大鼠中 L-NAME 阻断 NO 产生的效率较低。尽管老年 ZDF 大鼠的 eNOS 表达水平与老年 LZ 大鼠相似，但 L-NAME 对老年 ZDF 大鼠没有影响。超氧化物水平和 NADPH 氧化酶亚基（p67phox 和 gp91phox）在 ZDF 大鼠中的表达水平高于 LZ 大鼠，并且在 ZDF 大鼠中随年龄增长进一步增加。在年轻的 ZDF 大鼠中，用 tempol 减少超氧化物水平可将乙酰胆碱依赖性松弛恢复到 LZ 大鼠的水平。在老年 ZDF 大鼠中，tempol 改善了乙酰胆碱依赖性松弛，但未使其达到 LZ 大鼠的水平。COX-2（免疫标记和 Western blot）存在于 ZDF 大鼠的动脉中，而不存在于 LZ 大鼠的动脉中。在老年 ZDF 大鼠中，动脉 COX-2 水平高于年轻 ZDF 大鼠。用 NS398 阻断 COX-2 部分恢复了老年 ZDF 大鼠中乙酰胆碱依赖性松弛，而 tempol 和 NS398 的联合使用则完全恢复了对照（LZ 大鼠）水平的松弛。因此，超氧化物产生和 COX-2 衍生物共同降低了老年 ZDF 大鼠的内皮依赖性松弛，而超氧化物单独减弱了年轻 ZDF 或老年 LZ 大鼠的松弛。
