The effect of genomic instability on vascular angiotensin II responses： implications for aging of the renin-angiotensin system  

出　　处：《中国药理学通报》2015年第B11期59-59,共1页Chinese Pharmacological Bulletin

摘　　要：Aim Aging is the dominant risk factor for cardiovascular disease. Recently, we have shown that genom- ic instability, a causative mechanism of aging in general, induced by functional mutation of the ERCC1 DNA repair protein in mice （Erccl d/- mice） causes accelerated age-dependent vascular dysfunction and hypertension. The re- nin-angiotensin system （RAS） has been implicated in vascular aging and hypertension, in which an increased stim- ulation of angiotensin Ⅱ type 1 receptors （AT1 R） plays a central role by both causing genomic instability as well as vascular damage. We hypothesized that genomic instability causes increased responses to angiotensin Ⅱ and that treatment with AT1R antagonist losartan may impede vascular vasomotor dysfunction that arises from genomic insta- bility. Methods Male and female Erccl d/- and wild type （WT） mice from 5-weeks old were divided into two groups per strain, which were either treated with losartan, given in a dose of 100 mg· kg^-1 . d^-1 in drinking wa- ter, or with drinking water only. At the age of 11 weeks blood pressure （BLP） was measured in a subgroup of con- scious mice by tail-cuff technique. At 12 weeks of age the animals were sacrificed. Iliac arteries rings were used in organ baths to study the response to 60 mM KC1. Thereafter, angiotensin Ⅱ cumulative concentration response curves were constructed to detect the vasoconstrictor function. To investigate the involvement of cGMP signaling, a subgroup of segments was pre-incubated with ODQ （soluble guanylyl cyclase （sGC） inhibitor）. In addition, the vasodilator response to acetylcholine was measured in aortic rings. Results BLP tended to be increased in Er- eeld/- mice vs. WT （systolic BLP140 ＋7 vs128 ＋5 mmHg resp. ）. Losartan decreased BLP which reached a simi- lar value for both strains （systolic BP-0100 mmHg）. Angiotensin II response of iliac arteries relative to KC1 were increased in Erccld/- vs WT （54% ＋ 10% vs 19% ＋5% of KC1 at 10-7 tool · L^-1 angiotensin Ⅱ

关 键 词：肾素-血管紧张素系统 基因组不稳定性 血管紧张素II 血管老化 血管紧张素Ⅱ AT1R拮抗剂 血管紧张素1型受体 可溶性鸟苷酸环化酶 

分 类 号：R544.1[医药卫生—心血管疾病] R730.231.2[医药卫生—内科学]