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 p...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 , P 〈0.05）. Losartan-treated WT and Erccld/- showed significantly lowered angiotensin Ⅱ responses compared with control treatment. ODQ increased angiotensin Ⅱ responses, but did not fully abolish the difference of WT and Erccld/-in the control group. Erccld/- had lower acetylcholine responses than WT （P 〈 0. 001 ） , which was not improved by losartan treatment. Conclusions The results suggest that genomic instability causes an accelerated RAS aging phe- notype. Chronic losartan treatment prevented this change of RAS phenotype. The increased angiotensin II activity does not depend on changes in endothelial function or nitric oxide-cGMP signaling. Further analyses of the RAS in models of genomic instability are necessary to fully appreciate the role of this causal mechanism for aging.展开更多
文摘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 , P 〈0.05）. Losartan-treated WT and Erccld/- showed significantly lowered angiotensin Ⅱ responses compared with control treatment. ODQ increased angiotensin Ⅱ responses, but did not fully abolish the difference of WT and Erccld/-in the control group. Erccld/- had lower acetylcholine responses than WT （P 〈 0. 001 ） , which was not improved by losartan treatment. Conclusions The results suggest that genomic instability causes an accelerated RAS aging phe- notype. Chronic losartan treatment prevented this change of RAS phenotype. The increased angiotensin II activity does not depend on changes in endothelial function or nitric oxide-cGMP signaling. Further analyses of the RAS in models of genomic instability are necessary to fully appreciate the role of this causal mechanism for aging.
