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Rapid CommunicationAccelerated Communication

Increase in Cellular Cyclic AMP Concentrations Reverses the Profibrogenic Phenotype of Cardiac Myofibroblasts: A Novel Therapeutic Approach for Cardiac Fibrosis

David Lu, Nakon Aroonsakool, Utako Yokoyama, Hemal H. Patel and Paul A. Insel
Molecular Pharmacology December 2013, 84 (6) 787-793; DOI: https://doi.org/10.1124/mol.113.087742
David Lu
Departments of Pharmacology (D.L., N.A., U.Y., P.A.I.) and Medicine (P.A.I.), University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California (H.H.P.); Department of Anesthesiology, University of California, San Diego, La Jolla, California (H.H.P.); and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan (U.Y.)
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Nakon Aroonsakool
Departments of Pharmacology (D.L., N.A., U.Y., P.A.I.) and Medicine (P.A.I.), University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California (H.H.P.); Department of Anesthesiology, University of California, San Diego, La Jolla, California (H.H.P.); and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan (U.Y.)
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Utako Yokoyama
Departments of Pharmacology (D.L., N.A., U.Y., P.A.I.) and Medicine (P.A.I.), University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California (H.H.P.); Department of Anesthesiology, University of California, San Diego, La Jolla, California (H.H.P.); and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan (U.Y.)
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Hemal H. Patel
Departments of Pharmacology (D.L., N.A., U.Y., P.A.I.) and Medicine (P.A.I.), University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California (H.H.P.); Department of Anesthesiology, University of California, San Diego, La Jolla, California (H.H.P.); and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan (U.Y.)
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Paul A. Insel
Departments of Pharmacology (D.L., N.A., U.Y., P.A.I.) and Medicine (P.A.I.), University of California, San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California (H.H.P.); Department of Anesthesiology, University of California, San Diego, La Jolla, California (H.H.P.); and Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan (U.Y.)
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Abstract

Tissue fibrosis is characterized by excessive production, deposition, and contraction of the extracellular matrix (ECM). The second messenger cAMP has antifibrotic effects in fibroblasts from several tissues, including cardiac fibroblasts (CFs). Increased cellular cAMP levels can prevent the transformation of CFs into profibrogenic myofibroblasts, a critical step that precedes increased ECM deposition and tissue fibrosis. Here we tested two hypotheses: 1) myofibroblasts have a decreased ability to accumulate cAMP in response to G protein–coupled receptor (GPCR) agonists, and 2) increasing cAMP will not only prevent, but also reverse, the myofibroblast phenotype. We found that myofibroblasts produce less cAMP in response to GPCR agonists or forskolin and have decreased expression of several adenylyl cyclase (AC) isoforms and increased expression of multiple cyclic nucleotide phosphodiesterases (PDEs). Furthermore, we found that forskolin-promoted increases in cAMP or N6-phenyladenosine-cAMP, a protein kinase A–selective analog, reverse the myofibroblast phenotype, as assessed by the expression of collagen Iα1, α–smooth muscle actin, plasminogen activator inhibitor–1, and cellular contractile abilities, all hallmarks of a fibrogenic state. These results indicate that: 1) altered expression of AC and PDE isoforms yield a decrease in cAMP concentrations of cardiac myofibroblasts (relative to CFs) that likely contributes to their profibrotic state, and 2) approaches to increase cAMP concentrations not only prevent fibroblast-to-myofibroblast transformation but also can reverse the profibrotic myofibroblastic phenotype. We conclude that therapeutic strategies designed to enhance cellular cAMP concentrations in CFs may provide a means to reverse excessive scar formation following injury and to treat cardiac fibrosis.

Footnotes

    • Received June 7, 2013.
    • Accepted October 1, 2013.
  • D.L., N.A., and U.Y. contributed equally to this work.

  • This work was supported by research grants from the National Institutes of Health National Heart, Lung, and Blood Institute and National Institute on Aging [Grants HL091071, HL107200, HL066941, and F31AG39992]; a VA Merit Grant [BX001963] (to H.H.P.); grants (to U.Y.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Grant-in-Aid for Scientific Research on Innovative Areas [25116719]; the Yokohama Foundation for Advanced Medical Science; and the Takeda Science Foundation.

  • dx.doi.org/10.1124/mol.113.087742.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 84 (6)
Molecular Pharmacology
Vol. 84, Issue 6
1 Dec 2013
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Rapid CommunicationAccelerated Communication

cAMP Reverses the Cardiac Myofibroblast Phenotype

David Lu, Nakon Aroonsakool, Utako Yokoyama, Hemal H. Patel and Paul A. Insel
Molecular Pharmacology December 1, 2013, 84 (6) 787-793; DOI: https://doi.org/10.1124/mol.113.087742

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Rapid CommunicationAccelerated Communication

cAMP Reverses the Cardiac Myofibroblast Phenotype

David Lu, Nakon Aroonsakool, Utako Yokoyama, Hemal H. Patel and Paul A. Insel
Molecular Pharmacology December 1, 2013, 84 (6) 787-793; DOI: https://doi.org/10.1124/mol.113.087742
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