Abstract 78: Transforming Growth Factor-β Induces the Cardiac Fibrosis and Remodeling in Guanylyl cyclase/Natriuretic Peptide Receptor-A Gene-Disrupted Null Mutant Mice
Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) in mice exhibits high blood pressure, cardiac hypertrophy, fibrosis, and remodeling leading to congestive heart failure. The objective of this study was to determine the mechanisms regulating the development of fibrosis in Npr1 gene-disrupted mice hearts. The Npr1 null mutant (Npr1-/-, 0-copy), heterozygous (Npr1+/-, 1-copy), and wild-type (Npr1+/+, 2-copy) mice were administered by oral gavage with transforming growth factor-β1 (TGF- β1) receptor inhibitor GW788388 (1mg/kg/day) for 28 days. The heart tissues were isolated and used for quantification of fibrotic markers by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analyses. Together, systolic blood pressure (SBP), heart weight-to-body weight (HW/BW) ratio, left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), and percent fractional shortening (FS) were analyzed. The Npr1-/- null mutant mice hearts displayed 6-fold induction of fibrosis compared with wild-type (WT) Npr1+/+ mice. Furthermore, the increased expression of fibrotic markers as observed, including connective tissue growth factor (CTGF, 5-fold), α-smooth muscle actin (α-SMA, 4-fold) and TGF-β receptor I (TGF-βRI, 4-fold), TGF-β receptor II (TGF-βRII, 3.5-fold) and Smad2/3 proteins in Npr1-/- mice hearts compared with WT control mice. However, treatment with TGF-β receptor antagonist, GW788388, significantly prevented the cardiac fibrosis and down-regulated the expression of fibrotic markers and Smad proteins in Npr1-/- mice compared to vehicle-treated WT controls. The results of the present study suggest that the activation of cardiac fibrosis in Npr1-/- mice is mainly triggered through TGF-β mediated Smad-dependent pathways.
- natriuretic peptide receptor-A gene disruption
- transforming growth factor-ß
- Cardiac Fibrosis and remodeling
Author Disclosures: K.N. Pandey: None. U. Subramanian: None.
- © 2015 by American Heart Association, Inc.