TY - JOUR
T1 - Nucleotide excision DNA repair is associated with age-related vascular dysfunction
AU - Durik, Matej
AU - Kavousi, Maryam
AU - van der Pluijm, Ingrid
AU - Isaacs, Aaron
AU - Cheng, Caroline
AU - Verdonk, Koen
AU - Loot, Annemarieke E
AU - Oeseburg, Hisko
AU - Bhaggoe, Usha Musterd
AU - Leijten, Frank
AU - van Veghel, Richard
AU - de Vries, René
AU - Rudez, Goran
AU - Brandt, Renata
AU - Ridwan, Yanto R
AU - van Deel, Elza D
AU - de Boer, Martine
AU - Tempel, Dennie
AU - Fleming, Ingrid
AU - Mitchell, Gary F
AU - Verwoert, Germaine C
AU - Tarasov, Kirill V
AU - Uitterlinden, Andre G
AU - Hofman, Albert
AU - Duckers, Henricus J
AU - van Duijn, Cornelia M
AU - Oostra, Ben A
AU - Witteman, Jacqueline C M
AU - Duncker, Dirk J
AU - Danser, A H Jan
AU - Hoeijmakers, Jan H
AU - Roks, Anton J M
PY - 2012/7/24
Y1 - 2012/7/24
N2 - 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.
AB - 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.
KW - Aging/physiology
KW - Animals
KW - Blood Pressure/physiology
KW - Carotid Arteries/physiopathology
KW - Cells, Cultured
KW - Cellular Senescence/physiology
KW - DNA Repair/physiology
KW - DNA-Binding Proteins/genetics
KW - Endonucleases/genetics
KW - Endothelium, Vascular/pathology
KW - Femoral Artery/physiopathology
KW - Genomic Instability/physiology
KW - Humans
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Mutant Strains
KW - Models, Animal
KW - Polymorphism, Single Nucleotide/genetics
KW - Vascular Stiffness/physiology
KW - Xeroderma Pigmentosum Group D Protein/genetics
U2 - 10.1161/CIRCULATIONAHA.112.104380
DO - 10.1161/CIRCULATIONAHA.112.104380
M3 - Article
C2 - 22705887
SN - 0009-7322
VL - 126
SP - 468
EP - 478
JO - Circulation
JF - Circulation
IS - 4
ER -