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Publication
LNK deficiency promotes acute aortic dissection and rupture.
Authors Laroumanie F, Korneva A, Bersi MR, Alexander MR, Xiao L, Zhong X, Van Beusecum
JP, Chen Y, Saleh MA, McMaster WG, Gavulic KA, Dale BL, Zhao S, Guo Y, Shyr Y,
Perrien DS, Cox NJ, Curci JA, Humphrey JD, Madhur MS
Submitted By Submitted Externally on 12/12/2018
Status Published
Journal JCI insight
Year 2018
Date Published 10/1/2018
Volume : Pages 3 : Not Specified
PubMed Reference 30333305
Abstract Aortic dissection (AD) is a life-threatening vascular disease with limited
treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene,
encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to
acute AD and rupture in response to angiotensin (Ang) II infusion. As early as
day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas
display altered mechanical properties, increased elastin breaks, collagen
thinning, enhanced neutrophil accumulation, and increased MMP-9 activity
compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice
induces AD and rupture in response to Ang II, demonstrating that LNK deficiency
in hematopoietic cells plays a key role in this disease. Interestingly,
treatment with doxycycline prevents the early accumulation of aortic neutrophils
and significantly reduces the incidence of AD and rupture. PrediXcan analysis in
a biobank of more than 23,000 individuals reveals that decreased expression of
SH2B3 is significantly associated with increased frequency of AD-related
phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the
pathology of AD in experimental animals and humans and describe a new model that
can be used to inform both inherited and acquired forms of this disease.




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