Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands.
Circulation. 2012 Jul 24;126(4):468-78. doi: 10.1161/CIRCULATIONAHA.112.104380. Epub 2012 Jun 15.
Vascular dysfunction in atherosclerosis and diabetes mellitus, 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 resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (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 compared with 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.
在发达社会的老龄化人群中观察到的动脉粥样硬化和糖尿病中的血管功能障碍与血管 DNA 损伤和细胞衰老有关。我们假设，衰老过程中累积的 DNA 损伤会导致血管功能障碍。
在核苷酸切除修复基因 ERCC1 和 XPD 缺陷导致基因组不稳定的小鼠（Ercc1(d/-)和 Xpd(TTD)小鼠）中，我们比较了与野生型小鼠相比，随年龄增长的血管功能。Ercc1(d/-)小鼠表现出血管细胞衰老增加、血管舒张功能障碍加速发展、血管僵硬增加和血压升高，这些情况在非常年轻的时候就出现了。血管舒张功能障碍是由于内皮型一氧化氮合酶水平降低和平滑肌细胞功能受损所致，这涉及磷酸二酯酶活性。与 Ercc1(d/-)小鼠类似，Xpd(TTD)动物的年龄相关内皮依赖性血管舒张功能障碍也增加了。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与动脉僵硬之间的关联，发现 DDB2 基因假定启动子区域的单核苷酸多态性（rs2029298）与颈股脉搏波速度之间存在显著关联。
基因组不稳定的小鼠重现了在动物模型和人类中观察到的与年龄相关的血管功能障碍，但与野生型小鼠相比，其进展速度更快。此外，我们发现人类 DNA 修复基因的变异与血管僵硬的标志物之间存在关联，而血管僵硬与衰老有关。我们的研究支持了基因组不稳定性对心血管疾病发展有重要贡献的概念。
