Nucleotide excision DNA repair is associated with age-related vascular dysfunction.
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.


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.
Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands.
Matej
M
Durik
Maryam
M
Kavousi
Ingrid
I
van der Pluijm
Aaron
A
Isaacs
Caroline
C
Cheng
Koen
K
Verdonk
Annemarieke E
AE
Loot
Hisko
H
Oeseburg
Usha Musterd
UM
Bhaggoe
Frank
F
Leijten
Richard
R
van Veghel
René
R
de Vries
Goran
G
Rudez
Renata
R
Brandt
Yanto R
YR
Ridwan
Elza D
ED
van Deel
Martine
M
de Boer
Dennie
D
Tempel
Ingrid
I
Fleming
Gary F
GF
Mitchell
Germaine C
GC
Verwoert
Kirill V
KV
Tarasov
Andre G
AG
Uitterlinden
Albert
A
Hofman
Henricus J
HJ
Duckers
Cornelia M
CM
van Duijn
Ben A
BA
Oostra
Jacqueline C M
JC
Witteman
Dirk J
DJ
Duncker
A H Jan
AH
Danser
Jan H
JH
Hoeijmakers
Anton J M
AJ
Roks
D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002339:Carotid Arteries / Q000503:physiopathology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D005263:Femoral Artery / Q000503:physiopathology; D042822:Genomic Instability / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D059289:Vascular Stiffness / Q000502:physiology*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D051759:Xeroderma Pigmentosum Group D Protein; C497293:Ercc2 protein, mouse