Abstract
SIRT6, a member of the NAD (+)-dependent class III deacetylase sirtuin family, plays important roles in the maintenance of cardiovascular homeostasis. Telomere shortening is a risk factor for age-associated diseases, including heart disease. In the present study, we investigated the role of SIRT6 and telomerase in a mouse model of transverse aortic constriction (TAC)-induced heart failure. SIRT6, telomerase reverse transcriptase (TERT), and telomere repeat binding factor (TRF)-1 were significantly downregulated in TAC mice compared with their expression in sham-operated mice. Lentiviral vector-mediated overexpression of SIRT6 upregulated TERT and TRF1 and increased the survival of mice after TAC. Echocardiography and hemodynamic measurements as well as histological analyses indicated that SIRT6 overexpression attenuated TAC-induced heart dysfunction and decreased TAC-induced cardiac inflammatory responses, reducing cardiac fibrosis and decreasing infarct size. Taken together, our findings indicate that SIRT6 protects the myocardium against damage and this effect may be mediated by the modulation of telomeres. Our findings linking SIRT6 and telomere integrity in the heart warrant further investigation into the underlying mechanisms and support SIRT6 as a promising therapeutic target for the treatment of cardiovascular diseases.
Highlights
Sirtuins or silent information regulator (SIR) proteins are NAD-dependent histone deacetylases that function as regulators of cellular homeostasis through their involvement in energy metabolism, genomic stability, inflammation, oxidative stress, and senescence (Kupis et al, 2016)
The levels of SIRT6, telomerase reverse transcriptase (TERT), and TRF1 were measured in myocardial tissues of mice exposed to transverse aortic constriction (TAC) or sham surgery to explore the association of sirtuins and telomere function with TAC-induced heart failure
The effect of SIRT6 was further analyzed by injection of a vector expressing SIRT6 lentivirus plasmids into mice before TAC, which resulted in the effective overexpression of SIRT6 mRNA and protein in TAC and sham-operated mice, as indicated by Quantitative Real-Time RT-PCR (qRT-PCR) and western blot analysis (Figures 2A,B)
Summary
Sirtuins or silent information regulator (SIR) proteins are NAD-dependent histone deacetylases that function as regulators of cellular homeostasis through their involvement in energy metabolism, genomic stability, inflammation, oxidative stress, and senescence (Kupis et al, 2016). SIRT2 which is present predominantly in the cytoplasm, colocalizes with microtubules and is involved in the deacetylation of the main component of microtubules, α-tubulin. SIRT3 is a positive regulator of mitochondrial activity by deacetylating and activating components of the electron transport chain and acetyl-CoA synthetase. SIRT3 is involved in the defense against oxidative stress. SIRT4, which is located in the mitochondrial matrix, suppresses the secretion of insulin and modulates ATP synthesis. SIRT5 is localized in the mitochondrial matrix, and deacetylates and activates carbamoyl synthetase 1, which catalyzes the first rate-limiting step of the urea cycle. SIRT7 interacts with and downregulates hypoxia-inducible factors HIF-1α
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
