Abstract 255: Lymphocyte-Specific Adaptor Protein, LNK (SH2B3), Regulates Angiotensin-II Induced Hypertension and Renal/Vascular Inflammation
LNK, an adaptor protein primarily expressed in hematopoietic cells and endothelial cells, is a negative regulator of cytokine signaling and cell proliferation. A single nucleotide polymorphism in LNK is associated with hypertension, but the mechanism is unknown. Our objective was to determine the effect of LNK on hypertension and inflammation using LNK-/- mice. In response to angiotensin II (Ang II) infusion, LNK-/- mice exhibit elevated systolic BP (SBP) compared to wild type C57Bl/6J mice (WT) as measured by telemetry. At baseline, kidneys from LNK-/- mice exhibit greater levels of total leukocyte and T lymphocyte infiltration, superoxide production, and albuminuria compared to WT mice, and these parameters are further exacerbated by AngII infusion. Aortas from LNK-/- mice exhibit enhanced inflammation, reduced nitric oxide production, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies showed that loss of LNK in hematopoietic cells (not somatic cells) reproduced the phenotype of whole body deletion of LNK with SBP reaching 180 mmHg in response to a subpressor dose of Ang II. Splenic T cells from LNK-/- mice produce elevated levels of interferon-gamma (IFNγ) compared to WT mice. Furthermore, IFNγ-/- mice exhibit blunted hypertension in response to AngII infusion, suggesting that enhanced IFNγ production is at least partly responsible for the aggravated hypertension in LNK-/- mice. Data are summarized in the table (expressed as mean±SEM, n=5-10,*P<0.05 vs WT/Sham, #P<0.05 vs WT/AngII and †P<0.05 vs LNK-/-/Sham). In conclusion, LNK may serve as a novel therapeutic target for hypertension and its associated renovascular disorders.
Author Disclosures: M.A. Saleh: None. W.G. McMaster: None. S.A. Funt: None. S.R. Thabet: None. J. Wu: None. L. Xiao: None. A.E. Norlander: None. W. Chen: None. H.A. Itani: None. T. Huan: None. D. Levy: None. D.G. Harrison: None. M.S. Madhur: None.
- © 2014 by American Heart Association, Inc.