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.
Fanny Laroumanie, Arina Korneva, Matthew R. Bersi, Matthew R. Alexander, Liang Xiao, Xue Zhong, Justin P. Van Beusecum, Yuhan Chen, Mohamed A. Saleh, William G. McMaster, Kyle A. Gavulic, Bethany L. Dale, Shilin Zhao, Yan Guo, Yu Shyr, Daniel S. Perrien, Nancy J. Cox, John A. Curci, Jay D. Humphrey, Meena S. Madhur
LNK deficiency induces early MMP-9 activity in the abdominal aorta prior to the development of AD.