Nucleotide excision DNA repair is associated with age-related vascular dysfunction.
Nucleotide excision DNA repair is associated with age-related vascular dysfunction.
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DOI：
10.1161/circulationaha.112.104380
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发表时间：
2012-07-24
期刊：
影响因子：
37.8
通讯作者：
Roks AJ
中科院分区：
文献类型：
--
作者：
Durik M;Kavousi M;van der Pluijm I;Isaacs A;Cheng C;Verdonk K;Loot AE;Oeseburg H;Bhaggoe UM;Leijten F;van Veghel R;de Vries R;Rudez G;Brandt R;Ridwan YR;van Deel ED;de Boer M;Tempel D;Fleming I;Mitchell GF;Verwoert GC;Tarasov KV;Uitterlinden AG;Hofman A;Duckers HJ;van Duijn CM;Oostra BA;Witteman JC;Duncker DJ;Danser AH;Hoeijmakers JH;Roks AJ
动脉粥样硬化和糖尿病中的血管功能障碍，如在发达社会的老龄化人口中观察到的，与血管DNA损伤和细胞衰老有关。我们假设，在衰老过程中累积的DNA损伤有助于血管功能障碍。在由于核苷酸切除修复基因ERCC 1和XPD缺陷而导致基因组不稳定的小鼠（Ercc 1d/−和XpdTTD小鼠）中，我们与野生型小鼠相比，探索了年龄依赖性血管功能。Ercc 1d/−小鼠在很小的时候就表现出血管细胞衰老增加，血管扩张功能障碍加速发展，血管僵硬增加和血压升高。血管舒张功能障碍是由于内皮eNOS水平降低以及平滑肌细胞功能受损，其中涉及磷酸二酯酶（PDE）活性。与Ercc 1d/−小鼠相似，XpdTTD动物中年龄相关的内皮依赖性血管舒张功能障碍增加。为了研究其对人类血管疾病的影响，我们在AortaGen联盟中探索了选定核苷酸切除修复基因的单核苷酸多态性（SNP）与动脉僵硬度之间的关联，并发现DDB 2基因推定启动子区的SNP（rs 2029298）与颈动脉-股动脉脉搏波速度显著相关。与野生型小鼠相比，具有基因组不稳定性的小鼠重现了在动物模型和人类中观察到的年龄依赖性血管功能障碍，但进展加速。此外，我们还发现了人类DNA修复基因的变异与血管硬度标记之间的关联，血管硬度与衰老有关。我们的研究支持基因组不稳定性对心血管疾病的发展有重要作用的概念。
Vascular dysfunction in atherosclerosis and diabetes, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. In mice with genomic instability due to the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1d/− and XpdTTD mice), we explored age-dependent vascular function as compared to wild-type mice. Ercc1d/− mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness and elevated blood pressure at very young age. The vasodilator dysfunction was due to decreased endothelial eNOS levels as well as impaired smooth muscle cell function, which involved phosphodiesterase (PDE) activity. Similar to Ercc1d/− mice, age-related endothelium-dependent vasodilator dysfunction in XpdTTD animals was increased. To investigate the implications for human vascular disease, we explored associations between single nucleotide polymorphisms (SNPs) of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium, and found a significant association of a SNP (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity. Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans, but with an accelerated progression, as compared to wild type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.