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.

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…In ANG II-treated human umbilical vein endothelial cells, the ACE inhibitor zofenoprilat inhibited superoxide production, cell apoptosis, and NF-kB activation and reverted SIRT1 downregulation; importantly, zofenoprilat downregulated AT 1 R protein expression through SIRT1 (268). Furthermore, when cells are under energy stress, the mRNA expression of ACE2, which counteracts ACE actions and seems to provide protection in cardiovascular disease, diabetes, and cancer, is controlled by SIRT1 activity (81). Finally, in a human model of endogenous AT 1 R antagonism, i.e., in patients with Bartter/Gitelman syndromes both of which are characterized by normal to low blood pressure, hypokalemia, and hypomagnesemia in the presence of high renin, ANG II, and aldosterone, among others, the protein expression of SIRT1 and the antioxidant enzyme heme oxygenase-1 in mononuclear cells was significantly higher than in untreated stage 1 essential hypertensive patients and healthy individuals (95).…”

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

“…These data suggest that ANG 1-7 induces renal ATGL expressions possibly via deacetylation of FOXO1 by SIRT1. We next determined renal ACE2 level in db/db mice since ACE2 is regulated by the SIRT1 pathway and in diabetic conditions (8,35). Immunofluorescence imaging showed increased ACE2 levels in renal cortical tubules in db/db mice, which was reversed by ANG 1-7 treatment (Fig.…”

Sirtuins in vascular diseases: Emerging roles and therapeutic potential

“…Under conditions of energy stress, SIRT1 activity 239 controls the expression of the ACE-2 transcript, whose enhanced 240 expression is protective in diabetes and CVD, as it counterbalances the 241 actions of ACE by metabolizing the vasoactive and fibrogenic peptide 242Ang II into angiotensin-(1-7)[62]. The epigenetic regulation of ACE-2 243 by SIRT1 occurs through the binding of SIRT1 to the ACE-2 promoter244 which is increased after treatment with the AMP mimic AICAR 245 (5-amino-4-imidazolecarboxamide riboside) and decreased after 246 IL-1β treatment[62].247 SIRT1 expression levels also influence cerebral artery relaxation via 248 endothelial-derived NO and mediate regeneration of blood vessels in is-249 chemic neuronal tissue, in part through the deacetylation of hypoxia-250 induced factor (HIF) 1α and 2α [63].…”

“…Under conditions of energy stress, SIRT1 activity 239 controls the expression of the ACE-2 transcript, whose enhanced 240 expression is protective in diabetes and CVD, as it counterbalances the 241 actions of ACE by metabolizing the vasoactive and fibrogenic peptide 242Ang II into angiotensin-(1-7)[62]. The epigenetic regulation of ACE-2 243 by SIRT1 occurs through the binding of SIRT1 to the ACE-2 promoter244 which is increased after treatment with the AMP mimic AICAR 245 (5-amino-4-imidazolecarboxamide riboside) and decreased after 246 IL-1β treatment[62].247 SIRT1 expression levels also influence cerebral artery relaxation via 248 endothelial-derived NO and mediate regeneration of blood vessels in is-249 chemic neuronal tissue, in part through the deacetylation of hypoxia-250 induced factor (HIF) 1α and 2α [63]. However, although endogenous 251 SIRT1 showed an important function as a stress-induced protector in a 252 mouse model of oxygen-induced proliferative retinopathy [63], recent 253 data indicate that overexpression of SIRT1 or treatment with small acti-254 vator molecules did not provide additional protection against retinopaof EC functionality for vascular repair and angiogenesis 258 is vital to the control of CVD and vascular complications of type 1 or type 259 2 diabetes.…”