GENETIC-DISRUPTION OF Npr1 LEADS TOCARDIAC HYPERTROPHY AND REMODELING: ROLE OF PRO-INFLAMMATORY CYTOKINES
Kailash N. Pandey, Ph.D., Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA
Genetic-disruption of guanylylcyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) exhibit cardiac hypertrophy and congestive heart failure similar to those seen in untreated human hypertensive subjects. The objective of this study was to determine whether ablation of NPRA/cGMP signaling in mice alters the expression of pro-inflammatory cytokines including; interleukin-6 (Il-6), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) leading to cardiac hypertrophy and remodeling in Npr1 homozygous null mutant (Npr1-/-) mice. The levels of Il-6, TNF-alpha, and TGF-beta1 in the left ventricular tissues were assayed by ELISA, Western blot analysis, and ribonuclease protection assay. The results showed that Il-6 and TNF-alpha levels were enhanced by 3-fold to 5-fold in the Npr1-/- mice hearts as compared with wild-type (Npr1+/+) mice hearts. The expression of TGF-beta1 and its receptor (TGF-beta1R) levels were greatly stimulated by almost 4-fold and 8-fold, respectively, in the hearts of Npr1 null mutant mice as compared with Npr1 wild-type control mice. The findings demonstrated that the reduced cGMP signaling results in the activation of pro-inflammatory cytokines gene expression, which leads to the development of cardiac hypertrophy and congestive heart failure in Npr1null mutant mice. The results suggest that disruption of the Npr1 gene leads to the augmented expression of cardiac nuclear factor kappa B (NF-kB)-mediated-signaling pathways that provoke the pro-inflammatory cytokines and promote the development of cardiac hypertrophy and remodeling in mice lacking GC-A/NPRA.