TY - JOUR
T1 - DNA Damage Response
T2 - A Molecular Lynchpin in the Pathobiology of Arteriosclerotic Calcification
AU - Duer, Melinda
AU - Cobb, Andrew M.
AU - Shanahan, Catherine M.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response- A complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.
AB - Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response- A complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature. Unexpectedly, a posttranslational modification, PAR (poly[ADP-ribose]), which is a byproduct of the DNA damage response, initiates biomineralization by acting to concentrate calcium into spheroidal structures that can nucleate apatitic mineral on the ECM (extracellular matrix). As we start to dissect the molecular mechanisms driving aging-associated vascular calcification, novel treatment strategies to promote healthy aging and delay pathological change are being unmasked. Drugs targeting the DNA damage response and senolytics may provide new avenues to tackle this detrimental and intractable pathology.
KW - cell death
KW - DNA damage
KW - genome
KW - healthy aging
KW - humans
UR - http://www.scopus.com/inward/record.url?scp=85087110439&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.120.313792
DO - 10.1161/ATVBAHA.120.313792
M3 - Review article
C2 - 32404005
AN - SCOPUS:85087110439
SN - 1079-5642
SP - E193-E202
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
ER -