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.
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Research Article Aging

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

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

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Figure 1

Sirt3 is required to block cardiac hypertrophic response.

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Sirt3 is required to block cardiac hypertrophic response. (A) Expression...
(A) Expression levels of 2 forms of Sirt3 in different models of cardiac hypertrophy. Western blotting analysis of heart samples of mice subjected to chronic infusion of agonists, ISO, Ang II, or PE as well as of aortic banding (Band) or forced swimming exercise (exer). (B) Quantification of 2 forms of Sirt3 in different models of hypertrophy. (C) Percentage of cardiac hypertrophy in response to different stimuli. Values are mean ± SEM, n = 5–10. (D) HW/BW ratios of WT and Sirt3-KO mice infused with either vehicle (sham) or Ang II for 14 days. Values are mean ± SEM. (E) H&E-stained sections of hearts from WT and Sirt3-KO mice subjected to Ang II–mediated hypertrophy show gross changes of cardiac hypertrophy. (F) Sections of hearts stained with Masson’s trichrome to detect fibrosis (blue). (G) Heart sections stained with wheat germ agglutinin to demarcate cell boundaries. Original magnification, ×4 (E); ×40 (F); ×400 (G). (H and I) Quantification of fibrosis and myocyte cross-sectional area in control (sham) and Ang II–treated WT and Sirt3-KO mice hearts. (J) Anf and Myh7 mRNA levels in heart samples of control (sham) and Ang II–treated WT and Sirt3-KO mice. Mean ± SEM (n = 4–8). Cont, control.