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Blockade of nuclear factor‐kB signaling induces regression of cardiac hypertrophy in mice lacking natriuretic peptide receptor‐A
Author(s) -
Vellaichamy Elangovan,
Somanveen K,
Pandey Kailash N
Publication year - 2007
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.21.6.a1411-c
Subject(s) - npr1 , medicine , natriuretic peptide , endocrinology , heart failure , atrial natriuretic peptide , muscle hypertrophy , receptor , brain natriuretic peptide , npr2 , signal transduction , nfkb1 , biology , transcription factor , chemistry , microbiology and biotechnology , gene , biochemistry
Mice lacking Npr1 gene (encoding natriuretic peptide receptor‐A; NPRA) have hypertension and progressive cardiac hypertrophy. The objective of this study was to evaluate whether the inhibition of NF‐κB (nuclear factor kappa‐B) signaling can reverse the cardiac hypertrophy in mice lacking NPRA. We analyzed NF‐κB nuclear translocation, IKK‐kinase activity, and IκB‐α phosphorylation status in ventricular tissues of 16‐weeks old male Npr1 gene‐disrupted ( Npr1 −/− ) and wild‐type ( Npr1 +/+ ) mice. Electrophoretic mobility shift assay showed a significant increase (4‐fold; p<0.001) in the NF‐κB binding activity in the nuclear extract of Npr1 −/− mice hearts as compared with Npr1 +/+ mice hearts. Western analysis of p65 and p50 proteins in nuclear extracts indicated an increased translocation (3‐fold; p<0.01) of these subunits from the cytoplasm to the nucleus in Npr1 −/− mice hearts. Furthermore, mice treated with NF‐κB inhibitor pyrrolidine dithiocarbomate showed significantly reduced HW/BW ratio and NF‐κB binding activity as compared to untreated mutant mice hearts. Our findings suggest that in the absence of NPRA/cGMP signaling, an increased activation of NF‐κB may be the critical factor in promoting the pathways leading to cardiac hypertrophy and congestive heart failure in mice lacking NPRA. Supported by NIH Grant HL‐62147.