Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice.
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 approximately 200% 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.
Vakhrusheva
Olesya
O
Max-Planck-Institute for Heart and Lung Research, Department of Cardiac Development and Remodelling, Bad Nauheim, Germany.
Smolka
Christian
C
Gajawada
Praveen
P
Kostin
Sawa
S
Boettger
Thomas
T
Kubin
Thomas
T
Braun
Thomas
T
Bober
Eva
E
D000107:Acetylation; D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D024061:Collagen Type III / Q000378:metabolism; D004249:DNA Damage; D005355:Fibrosis; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D015398:Signal Transduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D024061:Collagen Type III; D016159:Tumor Suppressor Protein p53; D037761:Sirtuins