title: Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress.
abstract: ACE2 (angiotensin-converting enzyme 2) counterbalances the actions of ACE (angiotensin-converting enzyme) by metabolizing its catalytic product, the vasoactive and fibrogenic peptide AngII (angiotensin II), into Ang-(1-7) [angiotensin-(1-7)]. Enhanced ACE2 expression may be protective in diabetes, cardiovascular disease and cancer. However, relatively little is known about the specific physiological factors regulating ACE2 expression. In the present paper, we show, by Western blotting and qPCR (quantitative real-time PCR), that ACE2 expression is increased under conditions of cell stress, including hypoxic conditions, IL (interleukin)-1β treatment and treatment with the AMP mimic AICAR (5-amino-4-imidazolecarboxamide riboside). The NAD+-dependent deacetylase SIRT1 (silent information regulator T1) was found to be up-regulated after AICAR treatment but, conversely, was down-regulated after IL-1β treatment. ChIP analysis demonstrated that SIRT1 bound to the ACE2 promoter and that binding was increased after AICAR treatment, but decreased after IL-1β treatment. Inhibition of SIRT1 activity ablated the AICAR-induced increase in ACE2. In conclusion, we have established that the expression of the ACE2 transcript is controlled by the activity of SIRT1 under conditions of energy stress.
authors.affiliation: *School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Clarke
authors.affiliation: *School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Nikolai D
authors.initials: ND
authors.lastname: Belyaev
authors.affiliation: †Integrated Biosciences, School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, U.K.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lambert
authors.affiliation: *School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Turner
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000085962:Angiotensin-Converting Enzyme 2; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D044127:Epigenesis, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D012265:Ribonucleotides / Q000502:physiology; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C031143:AICA ribonucleotide