Abstract 12920: Transforming Growth Factor-Beta-Dependent Pathway Induces the Cardiac Fibrosis and Remodeling in Guanylyl Cyclase/Natriuretic Peptide Receptor-A Gene-Disrupted Mice
Introduction: Targeted-ablation of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) in mice exhibits hypertension and provokes congestive heart failure; however, the underlying mechanisms are not well understood.
Hypothesis: To determine whether transforming growth factor-beta 1 (TGF)-β1 receptor antagonist, GW788388 inhibits the development of cardiac fibrosis and remodeling in GC-A/NPRA gene-disrupted mice.
Methods: The adult male (16-20 weeks) Npr1 null mutant (Npr1-/-, 0-copy), heterozygous (Npr1+/-, 1-copy), and wild-type (Npr1+/+, 2-copy) mice were orally administered with TGF-β1 receptor antagonist, GW788388 (2 mg/kg/day) for 28 days. The expression of cardiac fibrotic markers was analyzed using real-time PCR and Western blot. Heart weight-to-body weight (HW/BW) ratios were determined and heart functions were measured by echocardiographic analysis.
Results: The Npr1-/- mice showed markedly increased cardiac fibrosis and HW/BW ratio with increased expression of collagen-1α (3.5-fold), monocyte chemoattractant protein (4-fold), connective tissue growth factor (CTGF, 5-fold), α-smooth muscle actin (α-SMA, 4-fold), TGF-βRI (4-fold), TGF-βRII (3.5-fold) and SMAD proteins (SMAD-2, 5-fold; SMAD-3, 3-fold) compared with Npr1+/+ mice. The expression of phosphorylated extracellular-regulated kinase (pERK1/2) was also up-regulated in Npr1-/- mice. The treatment of Npr1-/- mice with GW788388 significantly prevented the development of cardiac fibrosis and down-regulated the expression of fibrotic markers and SMAD proteins compared to vehicle-treated mice. In contrast, the expression of pERK1/2 proteins was unaffected in GW7885388-treated mice excluding the involvement of non-genomic pathway. The left ventricular dimensions (systole and diastole) and fractional shortening were significantly improved in the drug-treated Npr1-/- mice.
Conclusions: The results suggest that the cardiac fibrosis, remodeling, and dysfunction in Npr1-/- mice are regulated through TGF-β-mediated SMAD-dependent canonical pathway. The findings will be important for the development of new molecular therapeutic targets for the treatment of cardiac fibrosis, remodeling, and dysfunction in human patients.
Author Disclosures: U. Subramanian: None. V. Gogulamudi: None. I. Kessler: None. D. Chen: None. K.N. Pandey: None.
- © 2016 by American Heart Association, Inc.