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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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 5

Sirt3 inhibits activation of transcription and translation regulators involved in development of hypertrophy.

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Sirt3 inhibits activation of transcription and translation regulators in...
(A and B) Rat cardiomyocytes were infected with Ad.Sirt3 or Ad.Smut viruses and then stimulated with either vehicle or PE (20 μM) for 2 hours. Cells were stained for GATA4 (A) or NFAT (B), and subcellular localization of factors was determined by confocal microscopy. Positions of nuclei were determined by DAPI stain (blue). Original magnification, ×630 (A and B). (C) Cardiomyocytes were infected with viruses and treated with PE as in A. Cytoplasmic (Cyto) and nuclear (Nucl) fractions of myocytes were generated and analyzed by Western blotting. (D) Cardiomyocytes expressing the indicated adenoviruses were transfected with a basic luciferase plasmid (B-Luc) or NFAT-responsive/luciferase (NFAT-Luc) reporter plasmid. On the second day after transfection, cells were treated with PE (20 μM), and the luciferase activity was determined 24 hours after transfection. Values are normalized with the protein content of the cell (mean ± SEM, n = 5). (E) Cardiomyocytes were infected with the indicated adenoviruses and induced with PE (20 μM). Cells were harvested at different time points after PE treatment, and the lysate was analyzed by Western blotting. (F and G) Heart extracts of mice subjected to Ang II–mediated hypertrophy were analyzed by Western blotting. Results are shown for 2 mice of the same group. WT and N-Tg mice are controls of the same genetic background for Sirt3-KO and Sirt3-Tg mice, respectively.