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(Circulation Research. 2008;102:185.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Atrial Natriuretic Peptide Inhibits Transforming Growth Factor β–Induced Smad Signaling and Myofibroblast Transformation in Mouse Cardiac Fibroblasts

Peng Li^*, Dajun Wang^*, Jason Lucas, Suzanne Oparil, Dongqi Xing, Xu Cao, Lea Novak, Matthew B. Renfrow, Yiu-Fai Chen

From the Vascular Biology and Hypertension Program (P.L., D.W., J.L., S.O., D.X., Y.-F.C.), Department of Medicine; Department of Pathology (X.C., L.N.); and University of Alabama Biomedical FT-ICR MS Laboratory (M.B.R.), Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham.

Correspondence to Yiu-Fai Chen, PhD, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294. E-mail yfchen{at}uab.edu

This study tested the hypothesis that activation of atrial natriuretic peptide (ANP)/cGMP/protein kinase G signaling inhibits transforming growth factor (TGF)-β1–induced extracellular matrix expression in cardiac fibroblasts and defined the specific site(s) at which this molecular merging of signaling pathways occurs. Left ventricular hypertrophy and fibrosis, collagen deposition, and myofibroblast transformation of cardiac fibroblasts in response to pressure overload by transverse aortic constriction were exaggerated in ANP-null mice compared with wild-type controls. ANP and cGMP inhibited TGF-β1–induced myofibroblast transformation, proliferation, collagen synthesis, and plasminogen activator inhibitor-1 expression in cardiac fibroblasts isolated from wild-type mice. Following pretreatment with cGMP, TGF-β1 induced phosphorylation of Smad3, but the resultant pSmad3 could not be translocated to the nucleus. pSmad3 that had been phosphorylated with recombinant protein kinase G-1 was analyzed by use of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and ion trap tandem mass spectrometry. The analysis revealed phosphorylation of Ser309 and Thr388 residues, sites distinct from the C-terminal Ser423/425 residues that are phosphorylated by TGF-β receptor kinase and are critical for the nuclear translocation and down-stream signaling of pSmad3. These results suggest that phosphorylation of Smad3 by protein kinase G is a potential molecular mechanism by which activation of ANP/cGMP/protein kinase G signaling disrupts TGF-β1–induced nuclear translocation of pSmad3 and downstream events, including myofibroblast transformation, proliferation, and expression of extracellular matrix molecules in cardiac fibroblasts. We postulate that this process contributes to the antifibrogenic effects of the natriuretic peptide in heart.

Key Words: atrial natriuretic factor • transforming growth factor • cardiac fibroblast • cardiac fibrosis and remodeling • signal transduction

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Cyclic GMP/Protein Kinase G Phosphorylation of Smad3 Blocks Transforming Growth Factor-β–Induced Nuclear Smad Translocation: A Key Antifibrogenic Mechanism of Atrial Natriuretic Peptide

Iain L.O. Buxton and Dayue Duan
Circ. Res. 2008 102: 151-153. [Full Text] [PDF]

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				I. L.O. Buxton and D. Duan Cyclic GMP/Protein Kinase G Phosphorylation of Smad3 Blocks Transforming Growth Factor-{beta}-Induced Nuclear Smad Translocation: A Key Antifibrogenic Mechanism of Atrial Natriuretic Peptide Circ. Res., February 1, 2008; 102(2): 151 - 153. [Full Text] [PDF]