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Salt Exacerbates Development of Aortic Dissection and Rupture in LNK/SH2B3 Deficient Mice
Author(s) -
LAROUMANIE Fanny,
Saleh Mohamed A.,
McMaster William,
Kirabo Annet,
Madhur Meenakshi s.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1177.18
Subject(s) - medicine , angiotensin ii , inflammation , aortic dissection , endocrinology , cytokine , aorta , immunology , receptor
Background Inflammation plays a key role in the development of aortic dissection. In particular, the Th1 cytokine IFNγ has been detected in patients with aortic dissection. A polymorphism in the gene SH2B3 encoding the lymphocyte adaptor protein, LNK, is associated with hypertension and other cardiovascular and autoimmune diseases in human. We previously showed that mice deficient in LNK have exacerbated hypertension, enhanced T cell production of IFNγ and increased aortic inflammation. Salt has been shown to modulate T cell polarization. We hypothesized that LNK deficiency promotes aortic dissection/rupture at least in part through enhanced production of IFNγ, and that this is exacerbated by salt. Methods LNK −/− mice or wild type (WT) controls were infused with angiotensin II (1000 ng/kg/min) for 14 days with or without an initial intraperitoneal injection of saline equal to 10% of their body weight. Kaplan‐Meier survival curves were generated and flow cytometry, histology, and quantitative RT‐PCR were employed to evaluate aortic inflammation, remodeling, and gene expression. Results LNK −/− mice infused with angiotensin II exhibited an accelerated rate of suprarenal aortic dissection or rupture compared to WT mice, and this was exacerbated by salt injection ( Figure). Aortas from LNK −/− mice treated with salt plus angiotensin II expressed higher mRNA levels of IFNγ (2.8 fold increase, p<0.05) and the Th1 transcription factor T‐bet (6.2 fold increase, p<0.05) compared to aortas from WT mice that underwent the same treatment. Moreover, the aortic expression of the metalloproteinase MMP‐9 was upregulated compared to WT mice. In mice that developed aortic rupture, loss of LNK was associated with a decrease in the aortic expression of both pro collagens type 1 and 3. Conclusion Loss of LNK combined with salt exacerbates the development of aortic dissection and rupture. Targeting LNK and reducing salt intake may be a potential therapeutic strategy for the management of aortic dissections. Support or Funding Information The Fondation pour la Recherche Medicale (FRM)