Blockade of Cardiac Hypertrophy and Fibrosis by TGF‐Beta 1 Receptor Antagonist in Npr1 Gene‐Knockout Mice

Abstract

Genetic disruption of guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) gene (Npr1) in mice triggers cardiac hypertrophy, fibrosis, and remodeling associated with heart failure. However, the specific mechanisms of cardiac defects in Npr1 null mutant mice is not well understood. The objective of this study was to determine the mechanisms regulating the development of cardiac hypertrophy and fibrosis in Npr1 gene‐knockout mice. The Npr1 null mutant (Npr1−/−, 0‐copy), heterozygous (Npr1+/−, 1‐copy), and wild‐type (Npr1+/+, 2‐copy) mice were orally administered with transforming growth factor‐beta 1 (TGF‐β1) receptor antagonist GW788388 (1 mg/kg/day) for 28 days, the hearts were isolated, weighted, and used for quantification of hypertrophic and fibrotic markers using 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, and cardiac fibrosis were analyzed. HW/BW ratio was significantly higher in Npr1 knockout mice than wild‐type control mice. The Npr1−/− mice showed significant induction of cardiac hypertrophy and fibrosis with markedly induced expression of hypertrophic marker collagen‐1α (3.5‐fold) and fibrotic markers monocyte chemoattractant protein (4‐fold), connective tissue growth factor (CTGF, 5‐fold), alpha‐smooth muscle actin (α‐SMA, 4‐fold), and SMAD proteins (SMAD‐2, 5‐fold; SMAD‐3, 3‐fold) compared with wild‐type control mice. In addition, the expression of phosphorylated extracellular‐regulated kinase 1/2 (pERK1/2) proteins were also increased in Npr1−/−mice. On the other hand, Npr1−/−mice treated with GW788388 showed significant inhibition of cardiac hypertrophy and fibrosis and reduced expression of fibrotic markers and SMAD proteins compared to vehicle‐treated wild‐type mice. In contrast, the expressions of pERK1/2 proteins were unaffected in drug‐treated animals. The results of the present study suggest that development of cardiac hypertrophy and fibrosis in Npr1−/− mice is regulated independently through TGF‐β1‐mediated SMAD‐dependent pathways.Support or Funding InformationThis work was supported by NIH grants (HL057531 and HL062147).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.