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Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies.

Publication ,  Journal Article
Zhang, L; Connelly, JJ; Peppel, K; Brian, L; Shah, SH; Nelson, S; Crosslin, DR; Wang, T; Allen, A; Kraus, WE; Gregory, SG; Hauser, ER; Freedman, NJ
Published in: Hum Mol Genet
July 15, 2010

Aging is believed to be among the most important contributors to atherosclerosis, through mechanisms that remain largely obscure. Serum levels of tumor necrosis factor (TNF) rise with aging and have been correlated with the incidence of myocardial infarction. We therefore sought to determine whether genetic variation in the TNF receptor-1 gene (TNFR1) contributes to aging-related atherosclerosis in humans and whether Tnfr1 expression aggravates aging-related atherosclerosis in mice. With 1330 subjects from a coronary angiography database, we performed a case-control association study of coronary artery disease (CAD) with 16 TNFR1 single-nucleotide polymorphisms (SNPs). Two TNFR1 SNPs significantly associated with CAD in subjects >55 years old, and this association was supported by analysis of a set of 759 independent CAD cases. In multiple linear regression analysis, accounting for TNFR1 SNP rs4149573 significantly altered the relationship between aging and CAD index among 1811 subjects from the coronary angiography database. To confirm that TNFR1 contributes to aging-dependent atherosclerosis, we grafted carotid arteries from 18- and 2-month-old wild-type (WT) and Tnfr1(-/-) mice into congenic apolipoprotein E-deficient (Apoe(-/-)) mice and harvested grafts from 1 to 7 weeks post-operatively. Aged WT arteries developed accelerated atherosclerosis associated with enhanced TNFR1 expression, enhanced macrophage recruitment, reduced smooth muscle cell proliferation and collagen content, augmented apoptosis and plaque hemorrhage. In contrast, aged Tnfr1(-/-) arteries developed atherosclerosis that was indistinguishable from that in young Tnfr1(-/-) arteries and significantly less than that observed in aged WT arteries. We conclude that TNFR1 polymorphisms associate with aging-related CAD in humans, and TNFR1 contributes to aging-dependent atherosclerosis in mice.

Duke Scholars

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2010

Volume

19

Issue

14

Start / End Page

2754 / 2766

Location

England

Related Subject Headings

  • Up-Regulation
  • Receptors, Tumor Necrosis Factor, Type I
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Mice, Knockout
  • Mice
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity
 

Citation

APA
Chicago
ICMJE
MLA
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Zhang, L., Connelly, J. J., Peppel, K., Brian, L., Shah, S. H., Nelson, S., … Freedman, N. J. (2010). Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies. Hum Mol Genet, 19(14), 2754–2766. https://doi.org/10.1093/hmg/ddq172
Zhang, Lisheng, Jessica J. Connelly, Karsten Peppel, Leigh Brian, Svati H. Shah, Sarah Nelson, David R. Crosslin, et al. “Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies.Hum Mol Genet 19, no. 14 (July 15, 2010): 2754–66. https://doi.org/10.1093/hmg/ddq172.
Zhang L, Connelly JJ, Peppel K, Brian L, Shah SH, Nelson S, et al. Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies. Hum Mol Genet. 2010 Jul 15;19(14):2754–66.
Zhang, Lisheng, et al. “Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies.Hum Mol Genet, vol. 19, no. 14, July 2010, pp. 2754–66. Pubmed, doi:10.1093/hmg/ddq172.
Zhang L, Connelly JJ, Peppel K, Brian L, Shah SH, Nelson S, Crosslin DR, Wang T, Allen A, Kraus WE, Gregory SG, Hauser ER, Freedman NJ. Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies. Hum Mol Genet. 2010 Jul 15;19(14):2754–2766.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2010

Volume

19

Issue

14

Start / End Page

2754 / 2766

Location

England

Related Subject Headings

  • Up-Regulation
  • Receptors, Tumor Necrosis Factor, Type I
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Mice, Knockout
  • Mice
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetics & Heredity