Abstract 84: Deficiency of Lymphocyte-Specific Adaptor Protein, LNK, Exacerbates Angiotensin II-Induced Hypertension and Inflammation
Lymphocyte-specific adaptor protein, LNK, is a negative regulator of hematopoiesis and endothelial cell signaling. Several large-scale genome wide association studies have identified a non-synonymous single nucleotide polymorphism in exon 3 of LNK, also known as SH2B3, to be positively associated with both systolic and diastolic blood pressure. The mechanism by which LNK contributes to blood pressure regulation is unknown. As LNK is a negative regulator of cytokine signaling and cell proliferation, we hypothesized that loss of LNK would exacerbate angiotensin II (AngII)-induced hypertension and its associated inflammation. We found that mice deficient in LNK (LNK-/-) had similar baseline blood pressures compared to wild type C57Bl/6 (WT) mice. However, after 2 weeks of AngII infusion, LNK-/- mice exhibited a greater increase in systolic blood pressure (SBP) and decrease in HR compared to WT mice as measured by radiotelemetry (SBP: 196.0±5.8 vs 174.3±4.4 mmHg, p<0.01; HR: 533.3±14.4 vs 612.2±2.0 beats/min, p<0.05, n=6-7). Renal inflammation was examined by immunostaining and flow cytometry. At baseline, LNK-/- mice had almost 4-fold more CD3+ T cells in the renal medulla compared to WT mice (56.3±8.2/mm2 vs 14.8±3.9/mm2, p<0.01, n=3-4), and this was markedly increased in response to 2 weeks of AngII infusion (134.0±27.0/mm2 vs 32.5±5.9/mm2, p<0.01, n=3-4). Flow cytometry for total renal lymphocytes and activated macrophages demonstrated increased numbers of these cells both at baseline and in response to AngII infusion in the LNK-/- mice compared to WT mice. Cytokine analysis performed on the culture supernatants of splenic T cells demonstrated that baseline levels of interleukin 17A (IL17A) and tumor necrosis factor alpha were higher in LNK-/- mice compared to WT mice. The pro-inflammatory cytokine, IL17A, was further increased in LNK-/- mice in response to AngII infusion. Taken together, these data demonstrate that LNK inhibits AngII-induced hypertension and inflammation and might serve as a novel therapeutic target for this widespread disease.
- © 2013 by American Heart Association, Inc.