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 , . JCI insight. 2018 10 18; 3(20).

PMID: 30333305 [PubMed].
PMCID: PMC6237478.

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.

Tags: Faculty Publications 2018