Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • 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
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice
Nagalingam R. Sundaresan, … , Ayman Isbatan, Mahesh P. Gupta
Nagalingam R. Sundaresan, … , Ayman Isbatan, Mahesh P. Gupta
Published August 3, 2009
Citation Information: J Clin Invest. 2009;119(9):2758-2771. https://doi.org/10.1172/JCI39162.
View: Text | PDF
Research Article Aging Article has an altmetric score of 2

Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice

  • Text
  • PDF
Abstract

Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased expression of SIRT3 has been linked to an extended life span in humans. Here, we have shown that Sirt3 protects the mouse heart by blocking the cardiac hypertrophic response. Although Sirt3-deficient mice appeared to have normal activity, they showed signs of cardiac hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced a severe cardiac hypertrophic response, whereas Sirt3-expressing Tg mice were protected from similar stimuli. In primary cultures of cardiomyocytes, Sirt3 blocked cardiac hypertrophy by activating the forkhead box O3a–dependent (Foxo3a-dependent), antioxidant–encoding genes manganese superoxide dismutase (MnSOD) and catalase (Cat), thereby decreasing cellular levels of ROS. Reduced ROS levels suppressed Ras activation and downstream signaling through the MAPK/ERK and PI3K/Akt pathways. This resulted in repressed activity of transcription factors, specifically GATA4 and NFAT, and translation factors, specifically eukaryotic initiation factor 4E (elf4E) and S6 ribosomal protein (S6P), which are involved in the development of cardiac hypertrophy. These results demonstrate that SIRT3 is an endogenous negative regulator of cardiac hypertrophy, which protects hearts by suppressing cellular levels of ROS.

Authors

Nagalingam R. Sundaresan, Madhu Gupta, Gene Kim, Senthilkumar B. Rajamohan, Ayman Isbatan, Mahesh P. Gupta

×

Figure 10

A DN-Foxo3a eliminates the antihypertrophic effect of Sirt3.

Options: View larger image (or click on image) Download as PowerPoint
A DN-Foxo3a eliminates the antihypertrophic effect of Sirt3.
Cardiomyocy...
Cardiomyocytes were prepared from neonatal Sirt3-KO mice. They were infected with different combinations of adenoviruses as indicated and then stimulated with PE (20 μM) for 48 hours. (A) Measurement of [3H]-leucine incorporation into total cellular protein (mean ± SEM, n = 5; P < 0.01). (B) Immunostaining of cells with anti-ANF (red) and anti–α-actinin (green) antibodies. Positions of nuclei were determined by DAPI staining (blue). Original magnification, ×1,000. (C) The DN-Foxo3a inhibits the activity of endogenous Foxo3a. Cardiomyocytes were overexpressed with a Foxo3a responsive/luciferase reporter plasmid and viruses synthesizing Sirt3 or DN-Foxo3a in different combinations, as indicated. The luciferase activity was determined 48 hours after transfection. All values are normalized to protein content of the cell (mean ± SEM, n = 4; *P < 0.01). The DN-Foxo3a was capable of blocking Sirt3-dependent activation of Foxo-promoter activity. (D) Scheme illustrating signaling pathways modified by Sirt3 to block the cardiac hypertrophic response. Sirt3 levels are elevated during stress of cardiomyocytes, which deacetylates Foxo3a and traps it inside the nucleus to enhance the transcription of Foxo-dependent antioxidant genes, MnSOD and Cat. Increased expression of MnSOD and catalase suppresses ROS levels generated by stress stimuli. Because ROS is the second messenger of hypertrophic signaling pathways, suppression of ROS levels shuts down major signaling pathways involved in activation of transcription and translation events contributing to the cardiac hypertrophic response.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Mentioned by 1 peer review sites
Highlighted by 1 platforms
305 readers on Mendeley
3 readers on CiteULike
See more details