doi: 10.1161/CIRCRESAHA.107.170217
© 2008 American Heart Association, Inc.
Editorials |
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
From the Department of Pharmacology, University of Nevada School of Medicine, Reno.
Correspondence to Dayue Duan, MD, PhD, FAHA, Laboratory of Functional Genomics and Proteomics, Center of Biomedical Research Excellence, Department of Pharmacology, University of Nevada School of Medicine, Manville Medical Building Room #9/MS 318, Reno, NV 89557-0270. E-mail dduan@medicine.nevada.edu
See related article, pages 185–192
Key Words: cardiac remodeling • signal transduction • atrial natriuretic factor • transforming growth factor • protein kinase G • Smad phosphorylation • phosphoproteome
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
In response to hemodynamic overload, the heart undergoes a complex adaptive remodeling process that involves cardiac myocyte hypertrophy, transformation of fibroblast into myofibroblast, high-level expression of extracellular matrix (ECM) proteins, interstitial fibrosis, and cell death.1 Differentiation of cardiac fibroblasts into myofibroblasts is critical to the production and deposition of collagens and plays a decisive role in myocardial fibrosis and morphological alterations during the progression of adaptive myocardial hypertrophy to decompensation and heart failure.1,2
Among the plethora of identified fibrogenic factors, transforming growth factor (TGF)-β3 plays a fundamental role in hypertrophic and fibrotic remodeling of the heart, where it regulates cardiomyocyte growth, fibroblast activation, and ECM deposition.4,5 The expression of ventricular TGF-β mRNA and protein is increased in numerous models of pathological cardiac hypertrophy and in cardiac cells in response to putative hypertrophic stimuli.6,7 In vitro, TGF-β activates myofibroblast transformation and increases ECM production.7 Blockade of TGF-β signaling is predicted to blunt fibrosis.5 Recent studies from Chen et al8 convincingly demonstrated that disruption of TGF-β signaling by inducible dominant-negative mutation of the TGF-β receptor type II (TβRII) gene significantly reduced the pressure overload–induced myofibroblast transformation and interstitial fibrosis in mouse heart. Thus, there is considerable interest in understanding how signaling by TGF-β receptors is transduced and how the inevitable damage produced could be mitigated.
Of the 3 isoforms of TGF-β expressed in mammals,9,10 TGF-β1 is expressed in the adult heart, where it is secreted by cardiomyocytes and myofibroblasts and retained in significant amounts in ECM as a latent cytokine. Recent advances
Related Article:
Circ. Res. 2008 102: 185-192.