TY - JOUR
T1 - LNK deficiency promotes acute aortic dissection and rupture
AU - Laroumanie, Fanny
AU - Korneva, Arina
AU - Bersi, Matthew R.
AU - Alexander, Matthew R.
AU - Xiao, Liang
AU - Zhong, Xue
AU - Van Beusecum, Justin P.
AU - Chen, Yuhan
AU - Saleh, Mohamed A.
AU - McMaster, William G.
AU - Gavulic, Kyle A.
AU - Dale, Bethany L.
AU - Zhao, Shilin
AU - Guo, Yan
AU - Shyr, Yu
AU - Perrien, Daniel S.
AU - Cox, Nancy J.
AU - Curci, John A.
AU - Humphrey, Jay D.
AU - Madhur, Meena S.
PY - 2018/10/18
Y1 - 2018/10/18
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.122558
DO - 10.1172/jci.insight.122558
M3 - Article
C2 - 30333305
AN - SCOPUS:85063241678
VL - 3
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 20
ER -