Journal
PEPTIDES
Volume 28, Issue 4, Pages 893-899Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2006.12.009
Keywords
natriuretic peptide receptor-A; GC activity; cGMP signaling; cytokines
Funding
- NHLBI NIH HHS [HL-62147, R01 HL062147-08, R01 HL062147] Funding Source: Medline
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Natriuretic peptide receptor-A (NPRA) is the principal receptor for the cardiac hormones ANP and BNP. Mice lacking NPRA develop progressive cardiac hypertrophy and congestive heart failure. However, the mechanisms responsible for hypertrophic growth in the absence of NPRA signaling are not yet known. In the present study, we determined whether deficiency of NPRA/cGMP signaling alters the cardiac pro-inflammatory cytokines gene expression in Npr1 (coding for NPRA) gene-knockout (Npr1(-/-)) mice exhibiting cardiac hypertrophy and fibrosis as compared with control wild-type (Npr1(+/+)) mice. A significant up-regulation of cytokine genes such as TNF-alpha (five-fold), IL-6 (three-fold) and TGF-beta 1 (fourfold) were observed in mutant mice hearts lacking NPRA as compared with the age-matched wild-type mice. In parallel, NF-kappa B binding activity was almost five-fold greater in the nuclear extract of Npr1(-/-) mutant mice hearts as compared with wild-type Npr1(+/+) mice hearts. Guanylyl cyclase (GC) activity and cGMP levels were drastically reduced by 10- and 5-fold, respectively, in ventricular tissues of mutant mice hearts relative to wild-type controls. The present findings provide direct evidence that ablation of NPRA/cGMP signaling activates inflammatory cytokines, probably via NF-kappa B mediated signaling pathway, and is associated with hypertrophic growth of null mutant mice hearts. (c) 2006 Elsevier Inc. All rights reserved.
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