Abstract 068: Genetic Mechanisms Of Cardiac Hypertrophy And Fibrosis In Global Npr1 Gene-ablated Male And Female Mice

Abstract

Genetic ablation of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) in mice triggers cardiac remodeling associated with hypertrophy, fibrosis, and heart failure. The objective of this study was to determine the mechanisms regulating the developments of cardiac hypertrophy and fibrosis in global Npr1 (encoding NPRA) gene-knockout (KO) mice and whether transforming growth factor-beta 1 (TGF-β1) plays a critical role in this process. Both male and female Npr1 KO ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type (WT; Npr1 +/+ , 2-copy) mice were administered with TGF-β1 receptor antagonist GW788388 (2 mg/kg/day) by intraperitoneal (ip) injection for 28 days. The heart weight/body weight (HW/BW) and tibia length (TL) to BW (TL/BW) ratios were determined. Echocardiography was used to determine the cardiac structure and function. Quantitative polymerase chain reaction (qPCR) and Western blot were used to quantify the hypertrophic and fibrotic markers. HW/BW and TL/BW ratios were significantly higher in Npr1 KO mice and significantly greater in males than females. The Npr1 -/- mice showed significant induction of cardiac hypertrophic marker collagen-1α (3.5-fold) and fibrotic markers, monocyte chemoattractant protein (MCP, 4-fold), connective tissue growth factor (CTGF, 5-fold), alpha-smooth muscle actin (α-SMA, 4-fold) compared with WT mice. The expression of phosphorylated extracellular regulated kinase 1/2 (pERK1/2) was also upregulated in Npr1 -/- mice. Left ventricular end-systolic and diastolic dimensions (LVED-s, LEVD-d) and posterior wall thickness (PWT) were significantly increased in male KO mice than female KO mice compared with WT mice. The fractional shortening (FS) was compromised in male KO mice than female KO mice. The Treatment of Npr1 -/- mice with GW788388, prevented the development of cardiac hypertrophy and fibrosis compared to vehicle-treatment. The results suggest that the cardiac hypertrophy and fibrosis in Npr1 -/- mice is regulated through TGF-β1- SMAD-pathways.