Alvarez de Sotomayor Maria, Mingorance Carmen, Andriantsitohaina Ramaroson
Department of Pharmacology, Faculty of Pharmacy, University of Seville, C/Profesor Garcia-Gonzalez no. 2, 41012 Seville, Spain.
Atherosclerosis. 2007 Jul;193(1):112-20. doi: 10.1016/j.atherosclerosis.2006.08.041. Epub 2006 Sep 18.
This study was designed to test the hypothesis that fenofibrate, the peroxisome proliferator-activated receptor alpha (PPARalpha) activator, improves age-related endothelial dysfunction in small mesenteric arteries (SMA). Adult and aged rats were treated with fenofibrate and then endothelium-dependent relaxations of SMA; expressions of endothelial NO synthase (eNOS), cyclo-oxygenase (COX-1 and COX-2) and superoxide dismutases (SOD) (Cu/Zn SOD, Mn SOD and EC SOD) proteins and release of TXB(2) and 6-keto-PGF(1alpha) were assessed. Fenofibrate improved endothelium-dependent vasodilatation of arteries from old rats and decreased participation of endothelial vasoconstrictor products, sensitive to COX-1 and COX-2 inhibitors and acting on Tp receptor. Fenofibrate decreased expressions of COX-1 and COX-2, and generation of TXA(2). Release of vasodilator PGI(2) and U46619-induced contraction remained unaltered. Neither NO-mediated vasodilatation nor eNOS expression was affected. The addition of the scavengers, SOD and catalase increased relaxation only in SMA from control rats. Finally, fenofibrate did not change expressions of Cu/Zn SOD and Mn SOD but it increased EC SOD towards that observed in arteries from adult rats. Fenofibrate improves endothelial function in resistance arteries from aged rats by decreasing expression of COX-1 and COX-2 together with enhancing anti-oxidant capacity of the vessel wall probably through the increased expression of EC SOD. This study provides evidence that PPARalpha may have clinical applications toward maintaining endothelial function during ageing.
过氧化物酶体增殖物激活受体α（PPARα）激动剂非诺贝特可改善小肠系膜动脉（SMA）中与年龄相关的内皮功能障碍。对成年和老年大鼠给予非诺贝特治疗，然后检测SMA的内皮依赖性舒张功能；评估内皮型一氧化氮合酶（eNOS）、环氧化酶（COX-1和COX-2）和超氧化物歧化酶（SOD）（铜/锌超氧化物歧化酶、锰超氧化物歧化酶和细胞外超氧化物歧化酶）蛋白的表达以及血栓素B2（TXB2）和6-酮-前列腺素F1α（6-keto-PGF1α）的释放。非诺贝特改善了老年大鼠动脉的内皮依赖性血管舒张，并减少了对COX-1和COX-2抑制剂敏感且作用于血栓素受体的内皮血管收缩产物的参与。非诺贝特降低了COX-1和COX-2的表达以及血栓素A2（TXA2）的生成。血管舒张剂前列环素（PGI2）的释放和U46619诱导的收缩未发生改变。一氧化氮介导的血管舒张和eNOS表达均未受影响。添加超氧化物歧化酶和过氧化氢酶清除剂仅增加了对照大鼠SMA的舒张。最后，非诺贝特未改变铜/锌超氧化物歧化酶和锰超氧化物歧化酶的表达，但使其细胞外超氧化物歧化酶的表达增加至成年大鼠动脉中的水平。非诺贝特通过降低COX-1和COX-2的表达以及可能通过增加细胞外超氧化物歧化酶的表达来增强血管壁的抗氧化能力，从而改善老年大鼠阻力动脉的内皮功能。本研究提供了证据表明PPARα在衰老过程中维持内皮功能方面可能具有临床应用价值。
