SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity.
OBJECTIVE
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.


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.
Yu-Xuan
YX
Luo
Xiaoqiang
X
Tang
Xi-Zhou
XZ
An
Xue-Min
XM
Xie
Xiao-Feng
XF
Chen
Xiang
X
Zhao
De-Long
DL
Hao
Hou-Zao
HZ
Chen
De-Pei
DP
Liu
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000201:enzymology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D037761:Sirtuins / Q000502:physiology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*; D066253:Vascular Remodeling / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013482:Superoxide Dismutase; C514813:SIRT4 protein, mouse; D037761:Sirtuins
Cardiac hypertrophy; MnSOD; Oxidative stress; Sirt4