Loss of Lymphocyte Adaptor Protein LNK Predisposes to Acute Aortic Dissection

다국어 초록 (Multilingual Abstract)

Acute aortic dissection (AD) is a life‐threatening vascular disease associated with an inflammatory response. However, the precise immune cell types involved and the mechanisms are unknown. Interestingly, a polymorphism in the gene SH2B3 that encodes LNK has been associated with several cardiovascular and autoimmune diseases in humans. LNK is an adaptor protein expressed in hematopoietic and endothelial cells that negatively regulates cytokine signaling and cell proliferation. We hypothesize that LNK deficiency predisposes to AD.
Angiotensin II (Ang II) was infused for either 3 or 14 days into wild type (WT) and LNK−/− mice. Kaplan‐Meier survival curves were generated. After 3 days of Ang II infusion, biaxial mechanical tests on the abdominal aortas were performed. Aortic remodeling was evaluated by standard histological staining methods and quantitative RT‐PCR. Aortic inflammation was characterized by immunohistochemistry and flow cytometry. After 3 days of Ang II infusion, aortic gene expression profiles were analyzed by RNA sequencing.
LNK−/− mice infused with Ang II exhibit an accelerated rate of mortality compared to WT mice (66.6% vs 16.7% at day 14, P<0.001). Necropsies reveal that deaths are due to the development of AD or rupture, mainly localized in the supra‐renal abdominal aorta. Interestingly, during the phase that precedes the development of AD (3 days of Ang II infusion), the abdominal aorta from LNK−/− mice exhibit a decrease in energy storage capacity as well as adverse remodeling compared to WT mice. Elastin Van‐Gieson staining reveals more elastin fragmentation compared to WT mice (10.5 vs 4.6 breaks per section, P<0.01) and picrosirius red staining demonstrates less collagen deposition (3.3 vs 4.6 × 104 μm2, P<0.01). Moreover, the collagen fibers in LNK−/− aortas are composed of thinner fibers (4.1% vs 0.2%, P<0.05) and several areas of disruption on day 3 of Ang II infusion. Concomitantly, the aortic expression of MMPs 2, 9 and 12 are elevated in LNK−/− aortas compare to WT. Strikingly, the aorta of LNK−/− mice exhibit an increase in the number of neutrophils, macrophages and natural killer cells. RNA sequencing analysis identified “natural killer cell mediated cytotoxicity” as the most enriched category expressed by the aorta of LNK−/− mice compared to WT mice, prior to AD development.
LNK seems to play a key role in maintaining aortic wall integrity. Loss of LNK promotes deterioration of aortic tissue integrity and an exaggerated pro‐inflammatory response, composed primarily of innate immune cells, leading to the development of AD. Thus, targeting LNK could be a potential therapeutic strategy for the management of AD.
Support or Funding Information
American Heart Association Postdoctoral Fellowship, Greater Southeast Affiliate.
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.