Abstract P100: Gene Targeting of Npr1 Reveals Its Repressive Role in Cardiac Hypertrophy and Proinflammatory Cytokine Gene Expression

Abstract

The objective of the present study was to examine whether genetically determined differences in the Npr1 gene (coding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) affect the expression of cardiac pro-inflammatory cytokines and nuclear factor kappa-B (NF-kB) levels in Npr1 gene-targeted mice. The Npr1 gene-disrupted null mutant ( Npr1 −/− ; 0-copy) mice had 32-38 mmHg higher systolic blood pressure (SBP) and 60% greater heart weight to body weight (HW:BW) ratio, however, Npr1 gene-duplicated mice ( Npr1 ++/++ ; 4-copy) exhibited 10-15 mmHg lower SBP with no change in the HW:BW ratio compared with wild-type ( Npr1 +/+ ; 2-copy) mice. Significant up-regulation of interleukin-6 (IL-6; 2-fold tumor necrosis factor-alpha), TNF-α; 4-fold), and transforming growth factor-beta (TGF-β1; 4-fold), along with increases in NF-κB and activating protein-1 (AP-1) binding activities (170% and 130%, p < 0.01, respectively), were increased in the Npr1 −/− mice hearts. Conversely, a significant decrease in cytokine gene expression and NF-κB and AP-1 binding activities were found in gene-duplicated mice hearts compared with wild-type mice. The ventricular guanylyl cyclase (GC) activity and cGMP levels were reduced by almost 10-fold and 5-fold, respectively, in Npr1 -/- mice. However, GC activity and cGMP levels were increased, respectively, by almost 9-fold and 6-fold, respectively, in gene-duplicated mice. The present results provide direct evidence that duplication of Npr1 gene in mice represses the inflammatory cytokine gene expression via inhibition NF-κB- and AP-1-mediated signaling mechanisms, and is associated with cardiac protection.