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

Matej Durik, Maryam Kavousi, Ingrid van der Pluijm, Aaron Isaacs, Caroline Cheng, Koen Verdonk, Annemarieke E. Loot, Hisko Oeseburg, Usha Bhaggoe, Frank Leijten, Richard van Veghel, René de Vries, Goran Rudez, Renata Brandt, Yanto R. Ridwan, Elza D. van Deel, Martine F. de Boer, Dennie Tempel, Ingrid Fleming, Gary F. MitchellGermaine Verwoert, Kirill V. Tarasov, André Uitterlinden, Bert Hofman, Eric Duckers, Cornelia Duijn, Ben Oostra, JCM Witteman, Dirk-jan Duncker, Jan Danser, Jan Hoeijmakers, Anton Roks*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

112 Citations (Scopus)

Abstract

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 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.
Original languageEnglish
Pages (from-to)468-478
Number of pages11
JournalCirculation
Volume126
Issue number4
DOIs
Publication statusPublished - 15 Jun 2012

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