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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.

SUBMITTER: Laroumanie F

PROVIDER: S-EPMC6237478 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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LNK deficiency promotes acute aortic dissection and rupture.

Laroumanie Fanny F Korneva Arina A Bersi Matthew R MR Alexander Matthew R MR Xiao Liang L Zhong Xue X Van Beusecum Justin P JP Chen Yuhan Y Saleh Mohamed A MA McMaster William G WG Gavulic Kyle A KA Dale Bethany L BL Zhao Shilin S Guo Yan Y Shyr Yu Y Perrien Daniel S DS Cox Nancy J NJ Curci John A JA Humphrey Jay D JD Madhur Meena S MS

JCI insight 20181018 20

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 accu ...[more]

PMID: 30333305

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Project description:Acute aortic dissection (AAD) is one of the major aortic diseases that occurs without a preceding symptom and often results in sudden death. Despite the recent advances in cardiovascular medicine, AAD remains a serious problem because its molecular pathogenesis is largely unknown. In this paper, we report our serendipitous discovery that stress-induced expression of tenascin C (TNC), a member of matricellular proteins, is the protection mechanism of aorta to prevent AAD. The aortic wall stress imposed by the aortic stiffening and the angiotensin II infusion caused the strong induction of TNC in wild type mouse aorta without gross morphological changes. While TNC knockout mice at the baseline showed no morphological, histological or biomechanical abnormalities of aorta, deletion of TNC gene rendered the aorta susceptible to AAD upon the aortic stress. The stressed TNC-null aorta showed the loss of the tensile strength due to the insufficient expression of extracellular matrix proteins and the exaggerated proinflammatory response before the onset of AAD. Therefore, TNC works as a stress-activated molecular damper both by reinforcing the tensile strength and by limiting the excessive proinflammatory response in aorta. Thus far, the molecular event that leads to the AAD development has been unclear because of the unpredictable nature of the AAD onset. This study sheds light on the previously unrecognized tissue protection mechanism that converts the potentially harmful stress response into the active reinforcement of the aorta, of which failure leads to the development of AAD. Although TNC is expressed in various tissues upon the mechanical and proinflammatory stimuli, its role has long been a mystery. Our data uncovered the adaptive role of TNC in aorta that must be resilient to the continuous hemodynamic and humoral stress for lifetime. We used periaortic application of 0.5 M CaCl2 to the infrarenal aorta or either wild type (WT) or tenascin C knockout (TNC-KO) mice to create the mouse model for stiffened aorta and infused the mice with AngII (1 µg/min/kg) for 1 week to apply the pathological stress on aorta (Ca+AngII). Mice were then killed with an overdose of pentobarbital to obtain the tissue samples. The suprarenal aortic samples, from the level of right renal artery to 10 mm above the right renal artery, and infrarenal aortic samples, from the level of left renal artery to 10 mm below the left renal artery, were collected and kept in RNAlater (Qiagen) until the extraction of total RNA using RNeasy (Qiagen). We obtained the RNA samples from 8 mice with Ca+AngII treatment and 5 mice without Ca+AngII treatment for each genotype. We pooled the RNA samples with the identical experimental condition to perform the transcriptome analysis using Mouse Genome 430 2.0 (Affymetrix). We obtained suprarenal aortic smooth muscle cells (ASMCs) from TNC-KO mice by enzymatic dispersion and cultured them in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum. We cultured TNC-KO ASMCs in the presence or absence of exogenous TNC (10 µg/mL) and stimulated the cells with 10 ng/mL TNF-alpha for 24 h before obtaining total RNA using RNeasy. We used 3 independent ASMC cultures without the exogenous TNC and 4 independent cultures with the exogenous TNC. We hybridized each of the RNA samples individually to Mouse Genome 430 2.0 Array (Affymetrix).

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LNK deficiency promotes acute aortic dissection and rupture.

Publications

LNK deficiency promotes acute aortic dissection and rupture.

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