Nucleotide excision DNA repair is associated with age-related vascular dysfunction.
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 JCM., Duncker DJ., Danser AHJ., Hoeijmakers JH., Roks AJM.
BACKGROUND: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. METHODS AND RESULTS: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. CONCLUSIONS: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.