title: PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial.
abstract: Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients.
  
  
  
  To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs).
  
  
  
  Randomized, double-blind, placebo-controlled study in type 2 diabetes.
  
  
  
  A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected.
  
  
  
  Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT.
  
  
  
  Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile.
  
  
  
  Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fiore
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Gianfrilli
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannetta
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Galea
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Panio
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: di Dato
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pofi
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Pozza
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Sbardella
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Carbone
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Venneri
authors.affiliation: Department of Experimental Medicine (D.F., D.G., E.G., C.d.D., R.P., C.P., E.S., A.L., M.A.V., A.M.I.), Sapienza University of Rome, 00161 Rome, Italy; Department of Radiological, Oncological and Pathological Sciences (N.G., I.C.), Sapienza University of Rome, 00161 Rome, Italy; and Department of Anatomical, Histological, Forensic, and Orthopaedic Sciences (G.P., F.N.), Sapienza University, 00161 Rome, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
mesh_terms: D050154:Adiposity / Q000187:drug effects* / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004311:Double-Blind Method; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D058986:Phosphodiesterase 5 Inhibitors; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1