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Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice
Yang Zhang1, Xiaoman Wang1, Xun-Kai Li1
1Department of Biochemistry & Molecular Biology, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
Aims:
The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling.
Methods And Results:
Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans.
Conclusion:
The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66Shc-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.
Insights
The cytoplasmic deacetylase sirtuin 2 (SIRT2) delays vascular ageing by repressing p66Shc activation and mitochondrial reactive oxygen species. Reduced SIRT2 accelerates vascular ageing and age-related aortic diseases.
Area of Science:
- Vascular biology
- Gerontology
- Molecular mechanisms of ageing
Background:
- Ageing leads to vascular remodelling, but the underlying mechanisms are not fully understood.
- Sirtuin 2 (SIRT2), a cytoplasmic deacetylase, is investigated for its role in age-related vascular changes.
- Reduced SIRT2 activity is observed in aged aortas, suggesting a link to vascular ageing.
Purpose of the Study:
- To investigate the role and mechanisms of SIRT2 in ageing-induced vascular remodelling.
- To determine if SIRT2 influences vascular function and pathological remodelling during ageing.
- To explore SIRT2's potential as a therapeutic target for vascular rejuvenation.
Main Methods:
- Analysis of sirtuin expression using transcriptome and quantitative real-time PCR.
- Utilisation of young and old wild-type and Sirt2 knockout mice to assess vascular function.
- RNA-seq, histochemical staining, and biochemical assays to evaluate SIRT2's impact on vascular transcriptome and remodelling.
Main Results:
- SIRT2 levels are highest among sirtuins in human and mouse aortas and decrease with age.
- SIRT2 deficiency exacerbates age-related arterial stiffness, dysfunction, and aortic remodelling in mice.
- SIRT2 represses p66Shc activation and mitochondrial reactive oxygen species (mROS) by deacetylating p66Shc at lysine 81.
- Reduced SIRT2 expression correlates with age-related aortic diseases in humans.
Conclusions:
- SIRT2 acts as a crucial factor in delaying vascular ageing.
- The SIRT2-p66Shc-mROS axis in the cytoplasm-mitochondria pathway is vital for vascular ageing.
- SIRT2 represents a potential therapeutic target for promoting vascular rejuvenation.
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