title: Deletion of Sirt3 does not affect atherosclerosis but accelerates weight gain and impairs rapid metabolic adaptation in LDL receptor knockout mice: implications for cardiovascular risk factor development.
abstract: Sirt3 is a mitochondrial NAD(+)-dependent deacetylase that governs mitochondrial metabolism and reactive oxygen species homeostasis. Sirt3 deficiency has been reported to accelerate the development of the metabolic syndrome. However, the role of Sirt3 in atherosclerosis remains enigmatic. We aimed to investigate whether Sirt3 deficiency affects atherosclerosis, plaque vulnerability, and metabolic homeostasis. Low-density lipoprotein receptor knockout (LDLR(-/-)) and LDLR/Sirt3 double-knockout (Sirt3(-/-)LDLR(-/-)) mice were fed a high-cholesterol diet (1.25 % w/w) for 12 weeks. Atherosclerosis was assessed en face in thoraco-abdominal aortae and in cross sections of aortic roots. Sirt3 deletion led to hepatic mitochondrial protein hyperacetylation. Unexpectedly, though plasma malondialdehyde levels were elevated in Sirt3-deficient mice, Sirt3 deletion affected neither plaque burden nor features of plaque vulnerability (i.e., fibrous cap thickness and necrotic core diameter). Likewise, plaque macrophage and T cell infiltration as well as endothelial activation remained unaltered. Electron microscopy of aortic walls revealed no difference in mitochondrial microarchitecture between both groups. Interestingly, loss of Sirt3 was associated with accelerated weight gain and an impaired capacity to cope with rapid changes in nutrient supply as assessed by indirect calorimetry. Serum lipid levels and glucose tolerance were unaffected by Sirt3 deletion in LDLR(-/-) mice. Sirt3 deficiency does not affect atherosclerosis in LDLR(-/-) mice. However, Sirt3 controls systemic levels of oxidative stress, limits expedited weight gain, and allows rapid metabolic adaptation. Thus, Sirt3 may contribute to postponing cardiovascular risk factor development.
authors.affiliation: Division of Cardiology, Department of Medicine, University Hospital Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland, s.winnik@me.com.
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Gaul
authors.forename: Frédéric
authors.initials: F
authors.lastname: Preitner
authors.forename: Christine
authors.initials: C
authors.lastname: Lohmann
authors.forename: Julien
authors.initials: J
authors.lastname: Weber
authors.forename: Melroy X
authors.initials: MX
authors.lastname: Miranda
authors.forename: Yilei
authors.initials: Y
authors.lastname: Liu
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: van Tits
authors.forename: José María
authors.initials: JM
authors.lastname: Mateos
authors.forename: Chad E
authors.initials: CE
authors.lastname: Brokopp
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006706:Homeostasis; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D056566:Sirtuin 3 / Q000172:deficiency*
chemical_list: D011973:Receptors, LDL; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3