LNK deficiency promotes acute aortic dissection and rupture
Fanny Laroumanie, … , Jay D. Humphrey, Meena S. Madhur
Fanny Laroumanie, … , Jay D. Humphrey, Meena S. Madhur
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e122558. https://doi.org/10.1172/jci.insight.122558.
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Research Article Inflammation Vascular biology

LNK deficiency promotes acute aortic dissection and rupture

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.

Authors

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

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Figure 1

LNK deficiency predisposes to aortic dissection (AD) and rupture in angiotensin (Ang) II–infused mice.

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LNK deficiency predisposes to aortic dissection (AD) and rupture in angi...
(A) Kaplan-Meier survival curves of male WT and Lnk–/– mice during 14 days of Ang II infusion (n = 22–32). (B) Representative gross images of Ang II–infused WT and Lnk–/– aortas showing rupture and hematoma in the abdominal aorta. (C) Representative transverse section of dissected abdominal aorta from Ang II–infused Lnk–/– mice stained with hematoxylin and eosin (H&E). TL, true lumen; H, hematoma. (D) Representative immunohistochemical staining for neutrophils (Ly-6G/-6C) and macrophages (F4/80) in the dissected abdominal aorta of Ang II–infused Lnk–/– mice. Scale bars: 100 μm (C and D). (E) Representative transverse sections of abdominal aorta from Ang II–infused WT and Lnk–/– mice stained with H&E, Masson’s trichrome blue, and Elastica van Gieson. Arrows depict site of elastin degradation. Scale bars: 100 μm. (F) Kaplan-Meier survival curves of female WT and Lnk–/– mice during 14 days of Ang II infusion (n = 7–15). **P < 0.01 by Mantel-Cox test.