Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice

Abstract

Abstract-Sirt7 is a member of the mammalian sirtuin family consisting of 7 genes, Sirt1 to Sirt7, which all share a homology to the founding family member, the yeast Sir2 gene. Most sirtuins are supposed to act as histone/protein deacetylases, which use oxidized NAD in a sirtuin-specific, 2-step deacetylation reaction. To begin to decipher the biological role of Sirt7, we inactivated the Sirt7 gene in mice. Sirt7-deficient animals undergo a reduction in mean and maximum lifespans and develop heart hypertrophy and inflammatory cardiomyopathy. Sirt7 mutant hearts are also characterized by an extensive fibrosis, which leads to a 3-fold increase in collagen III accumulation. We found that Sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo and an increased rate of apoptosis in the myocardium of mutant mice. Sirt7-deficient primary cardiomyocytes show a Ϸ200% increase in basal apoptosis and a significantly diminished resistance to oxidative and genotoxic stress suggesting a critical role of Sirt7 in the regulation of stress responses and cell death in the heart. We propose that enhanced activation of p53 by lack of Sirt7-mediated deacetylation contributes to the heart phenotype of Sirt7 mutant mice. (Circ Res. 2008;102:703-710.)

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…Loss of white adipose tissue occurs in many progeroid syndromes, but whether this is due to persistent DNA damage has just started to be examined (Karakasilioti et al , 2013). Overall, our results provide the first evidence of an accelerated aging phenotype in SirT7 −/− mice, which is consistent with a previous SIRT7 KO mouse model showing hypertrophic cardiomyopathy and a shortened lifespan (Vakhrusheva et al , 2008b). …”

“…Deficiency of SIRT7 has been linked to several pathologies including cardiac hypertrophy (Vakhrusheva et al , 2008b; Ryu et al , 2014), hepatic steatosis (Shin et al , 2013; Ryu et al , 2014), and deafness (Ryu et al , 2014). SIRT7 has been functionally linked to transcriptional regulation.…”

Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins

“…SIRT6-knockout mice have aging-like phenotype, including severe hypoglycemia and loss of subcutaneous fat, leading to death at early age (Mostoslavsky et al, 2006;Xiao et al, 2010). SIRT7-knockout mice display cardiac hypertrophy (Vakhrusheva et al, 2008), whereas SIRT2-knockdown mice develop tumorigenesis, leading to the notion that SIRT2 acts as a tumor suppressor (Park et al, 2012). Mice lacking both SIRT3 alleles have higher levels of fatty-acid oxidation intermediate products and triglycerides during fasting, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice .…”

Sirtuins and inflammation: Friends or foes?

“…Vakhrusheva and coworkers have generated a SIRT7 knockout mouse and have shown that SIRT7 disruption predisposes the mice to heart hypertrophy together with increasing cardiac inflammation [51]. These authors observed an increased infiltration of immune cells (especially granulocytes) in SIRT7 -/-hearts, which correlated with constitutively higher levels of in situ pro-and anti-inflammatory cytokine production, in particular in aged mice.…”