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Telomere uncapping causes cellular senescence and inflammation in arteries: implications for arterial aging
Author(s) -
Morgan Richard G,
Ives Stephen J,
Lesniewski Lisa A,
Cawthon Richard M,
Andtbacka Robert HI,
Noyes R Dirk,
Denchi Eros L,
Richardson Russell S,
Donato Anthony J
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1131.1
Subject(s) - telomere , senescence , inflammation , cellular senescence , medicine , biology , immunology , dna , genetics , gene , phenotype
Telomere shortening has been associated with age‐related cardiovascular diseases. However, the uncapping of telomeres may have a greater impact on arterial aging, as it leads to cyclin dependent kinase inhibitor 1A (P21)‐induced senescence and subsequent inflammation. In arteries from 61 younger (YA) and older adults (OA), we assessed age‐related telomere uncapping (ChIP: p‐H2A.X (ser139) localization to telomeres), senescence (P21 mRNA ) and inflammation (TNFA , MCP1 mRNA ) . Aging leads to greater telomere uncapping (YA: 1.0±0.1 vs OA: 2.3±0.5, P = 0.02), as well as greater senescence ( P ≤ 0.04) and inflammation (both P < 0.06). Telomere uncapping was not associated with telomere shortening in human arteries (r = −0.09, P = 0.20). To provide proof of concept that telomere uncapping induces senescence and inflammation, we utilized a transgenic mouse model of inducible telomeric repeat factor 2 (trf2) deletion that results in telomere uncapping ( trf2 +/+ : 3.0±1.1 vs trf2 −/− : 4.7± 0.5, P = 0.07). There was greater senescence ( P < 0.03) and inflammation ( P ≤ 0.08) in aortas from trf2 −/− ( n = 6) compared with trf2 +/+ mice ( n = 8), despite no change in telomere length ( P = 0.49). Here we are the first to demonstrate age‐related telomere uncapping in human arteries and, using a novel mouse model of terf2 deletion, demonstrate that telomere uncapping induces senescence and inflammation in arteries. Support: NIA‐ AG040297 , U. CoA