Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Cdc42 is an antihypertrophic molecular switch in the mouse heart
Marjorie Maillet, … , Yi Zheng, Jeffery D. Molkentin
Marjorie Maillet, … , Yi Zheng, Jeffery D. Molkentin
Published September 8, 2009
Citation Information: J Clin Invest. 2009;119(10):3079-3088. https://doi.org/10.1172/JCI37694.
View: Text | PDF
Research Article Cardiology

Cdc42 is an antihypertrophic molecular switch in the mouse heart

  • Text
  • PDF
Abstract

To improve contractile function, the myocardium undergoes hypertrophic growth without myocyte proliferation in response to both pathologic and physiologic stimulation. Various membrane-bound receptors and intermediate signal transduction pathways regulate the induction of cardiac hypertrophy, but the cardioprotective regulatory pathways or effectors that antagonize cardiac hypertrophy remain poorly understood. Here we identify the small GTPase Cdc42 as a signaling intermediate that restrained the cardiac growth response to physiologic and pathologic stimuli. Cdc42 was specifically activated in the heart after pressure overload and in cultured cardiomyocytes by multiple agonists. Mice with a heart-specific deletion of Cdc42 developed greater cardiac hypertrophy at 2 and 8 weeks of stimulation and transitioned more quickly into heart failure than did wild-type controls. These mice also displayed greater cardiac hypertrophy in response to neuroendocrine agonist infusion for 2 weeks and, more remarkably, enhanced exercise-induced hypertrophy and sudden death. These pathologies were associated with an inability to activate JNK following stimulation through a MEKK1/MKK4/MKK7 pathway, resulting in greater cardiac nuclear factor of activated T cells (NFAT) activity. Restoration of cardiac JNK signaling with an Mkk7 heart-specific transgene reversed the enhanced growth effect. These results identify what we believe to be a novel antihypertrophic and protective cardiac signaling pathway, whereby Cdc42-dependent JNK activation antagonizes calcineurin-NFAT activity to reduce hypertrophy and prevent transition to heart failure.

Authors

Marjorie Maillet, Jeffrey M. Lynch, Bastiano Sanna, Allen J. York, Yi Zheng, Jeffery D. Molkentin

×

Figure 1

Generation of cardiac-specific CdcαMHC-cre mice.

Options: View larger image (or click on image) Download as PowerPoint
Generation of cardiac-specific CdcαMHC-cre mice.
   
(A) Western blot an...
(A) Western blot analysis of Cdc42 protein levels in 2-month-old WTαMHC-cre and CdcαMHC-cre hearts. GAPDH was used as a loading control. (B) Quantitation of the Western blot results shown in A. (C) Western blot analysis of total protein levels of RhoA and Rac1 in 2-month-old WTαMHC-cre and CdcαMHC-cre hearts. Rac baseline GTP loading for activity was also assayed. (D) Quantification of HW/BW at 1 year of age in WTαMHC-cre and CdcαMHC-cre animals. (E) Echocardiographic analysis of left ventricular FS in 1-year-old WTαMHC-cre and CdcαMHC-cre animals (n = 4 WTαMHC-cre and n = 3 CdcαMHC-cre). (F) H&E staining of longitudinal sections from hearts of WTαMHC-cre and CdcαMHC-cre mice at 1 year of age. (G) HW/BW at 1 week of age in WTαMHC-cre (n = 4) and CdcαMHC-cre (n = 6) mice. (H) Myocyte cell surface areas in heart histological sections at 1 week of age in WTαMHC-cre and CdcαMHC-cre mice. (I) Cdc42-GTP pull-down activity assay in neonatal rat cardiomyocytes stimulated for 10 minutes with the indicated hypertrophic agonists at 1 μM. A representative Western blot of 3 independent experiments is shown. (J) Rac1-GTP and Cdc42-GTP pull-down activity assays from hearts of sham- or TAC-operated WT mice subjected to TAC for 4, 7, or 14 days.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts