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Published on: April 21, 2010
SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase
Aims:
Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress.
Methods And Results:
Male C57BL/6 Sirt4 knockout mice, transgenic (Tg) mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II, 1.1 mg/kg/day). At 4 weeks, hypertrophic growth of cardiomyocytes, fibrosis and cardiac function were analysed. Sirt4 deficiency conferred resistance to Ang II infusion by significantly suppressing hypertrophic growth, and the deposition of fibrosis. In Sirt4-Tg mice, aggravated hypertrophy and reduced cardiac function were observed compared with non-Tg mice following Ang II treatment. Mechanistically, Sirt4 inhibited the binding of manganese superoxide dismutase (MnSOD) to Sirt3, another member of the mitochondrial sirtuins, and increased MnSOD acetylation levels to reduce its activity, resulting in elevated reactive oxygen species (ROS) accumulation upon Ang II stimulation. Furthermore, inhibition of ROS with manganese 5, 10, 15, 20-tetrakis-(4-benzoic acid) porphyrin, a mimetic of SOD, blocked the Sirt4-mediated aggravation of the hypertrophic response in Ang II-treated Sirt4-Tg mice.
Conclusions:
Sirt4 promotes hypertrophic growth, the generation of fibrosis and cardiac dysfunction by increasing ROS levels upon pathological stimulation. These findings reveal a role of Sirt4 in pathological cardiac hypertrophy, providing a new potential therapeutic strategy for this disease.
Insights
Sirt4 promotes cardiac hypertrophy and heart dysfunction by increasing oxidative stress. Inhibiting Sirt4 may offer a therapeutic strategy for pathological cardiac hypertrophy.
Area of Science:
- Mitochondrial biology
- Cardiovascular research
- Molecular mechanisms of disease
Background:
- Oxidative stress is a key factor in cardiac hypertrophy and heart failure.
- Sirt4, a mitochondrial sirtuin, is abundant in the heart, but its role is unclear.
Purpose of the Study:
- To investigate Sirt4's role in pathological cardiac hypertrophy.
- To elucidate the molecular mechanism of Sirt4 in regulating mitochondrial oxidative stress.
Main Methods:
- Utilized Sirt4 knockout and Sirt4-overexpressing mice treated with angiotensin II.
- Assessed cardiomyocyte hypertrophy, fibrosis, and cardiac function.
- Examined the interaction between Sirt4, Sirt3, and manganese superoxide dismutase (MnSOD) activity.
Main Results:
- Sirt4 deficiency protected against angiotensin II-induced cardiac hypertrophy and fibrosis.
- Cardiac-specific Sirt4 overexpression exacerbated hypertrophy and impaired cardiac function.
- Sirt4 increased MnSOD acetylation, reducing its activity and elevating reactive oxygen species (ROS).
- ROS inhibition blocked Sirt4-mediated cardiac dysfunction.
Conclusions:
- Sirt4 exacerbates pathological cardiac hypertrophy and fibrosis by increasing ROS levels.
- Sirt4 plays a critical role in cardiac dysfunction under pathological conditions.
- Targeting Sirt4 presents a potential therapeutic avenue for cardiac hypertrophy.
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