Nucleotide Excision DNA Repair Is Associated With Age-Related Vascular Dysfunction

作者：Durik Matej; Kavousi Maryam; van der Pluijm Ingrid; Isaacs Aaron; Cheng Caroline; Verdonk Koen; Loot Annemarieke E; Oeseburg Hisko; Bhaggoe Usha Musterd; Leijten Frank; van Veghel Richard; de Vries Rene; Rudez Goran; Brandt Renata; Ridwan Yanto R; van Deel Elza D; de Boer Martine; Tempel Dennie; Fleming Ingrid; Mitchell Gary F; Verwoert Germaine C; Tarasov Kirill V; Uitterlinden Andre G; Hofman Albert; Duckers Henricus J; van Duijn Cornelia M; Oostra Ben A

来源：Circulation, 2012, 126(4): 468-+.

DOI：10.1161/CIRCULATIONAHA.112.104380

• aging
• cardiovascular diseases
• endothelium
• nitric oxide synthase
• vasodilation

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. %26lt;br%26gt;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. %26lt;br%26gt;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. (Circulation. 2012;126:468-478.)

• 出版日期2012-7-24