Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress

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. Abbreviations: ACE, angiotensin-converting enzyme; ADAM17, a disintegrin and metalloproteinase 17; AICAR, 5-amino-4-imidazolecarboxamide riboside; AMPK, AMP-activated protein kinase; Ang-(1–7), angiotensin-(1–7); AngII, angiotensin II; ARDS, acute respiratory distress syndrome; CREB, cAMP-response-element-binding protein-binding protein; DMEM, Dulbecco’s modified Eagle’s medium; HDAC, histone deacetylase; IL-1β, interleukin-1β; Mca-APK-Dpn, (7-methoxycoumarin-4-yl)acetyl-Ala-Pro-Lys-2,4-dinitrophenyl; RAS, renin–angiotensin system; SIRT1, silent information regulator T1; T2DM, Type 2 diabetes mellitus