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

来源 :中国药理学会第十三次全国学术大会 | 被引量 : 0次 | 上传用户:zhenzhurujun
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  Aim Aging is the dominant risk factor for cardiovascular disease.Recently, we have shown that genomic instability, a causative mechanism of aging in general, induced by functional mutation of the ERCC1 DNA repair protein in mice (Erccl a/mice) causes accelerated agedependent vascular dysfunction and hypertension.The reninangiotensin system (RAS) has been implicated in vascular aging and hypertension, in which an increased stimulation of angiotensin Ⅱ type 1 receptors (AT1R) 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 AT1 R antagonist losartan may impede vascular vasomotor dysfunction that arises from genomic instability.Methods Male and female Erccld/and wild type (WT) mice from 5weeks old were divided into two groups per strain, which were either treated with losartan, given in a dose of 100 mg · kg1 · d1 in drinking water, or with drinking water only.At the age of 11 weeks blood pressure (BLP) was measured in a subgroup of conscious mice by tailcuff 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 KCl.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 preincubated 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 Erccld/mice vs.WT (systolic BLP140 ±7 vs128 ±5 mmHg resp.).Losartan decreased BLP which reached a similar value for both strains (systolic BP ~ 100 mmHg).Angiotensin Ⅱ response of iliac arteries relative to KCl were increased in Erccld/vs WT (54% ± 10% vs 19% ±5% of KC1 at 107 mol · L1 angiotensin Ⅱ, P <0.05).Losartantreated WT and Erccld/showed significandy 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.Ercc1d/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 phenotype.Chronic losartan treatment prevented this change of RAS phenotype.The increased angiotensin Ⅱ activity does not depend on changes in endothelial function or nitric oxidecGMP signaling.Further analyses of the RAS in models of genomic instability are necessary to fully appreciate the role of this causal mechanism for aging.
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