PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial

• Published in: The journal of clinical endocrinology and metabolism Vol. 101; no. 4; pp. 1525 - 1534
• Main Authors: Fiore, Daniela, Gianfrilli, Daniele, Giannetta, Elisa, Galea, Nicola, Panio, Giuseppe, di Dato, Carla, Pofi, Riccardo, Pozza, Carlotta, Sbardella, Emilia, Carbone, Iacopo, Naro, Fabio, Lenzi, Andrea, Venneri, Mary A., Isidori, Andrea M.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.04.2016; Copyright by The Endocrine Society
• Subjects: Adipose tissue; Adiposity - drug effects; Adiposity - genetics; Adult; Aged; Animal models; Animals; Biopsy; Body fat; Cardiomyocytes; Cardiovascular diseases; Cell culture; Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - physiopathology; DNA microarrays; Double-Blind Method; Flow Cytometry; Gene expression; Heart; Humans; Inflammation; Magnetic resonance imaging; Male; Mice; Mice, Obese; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Obesity, Abdominal - drug therapy; Obesity, Abdominal - metabolism; Obesity, Abdominal - pathology; Phosphodiesterase 5 Inhibitors - pharmacology; Placebos; Real-Time Polymerase Chain Reaction; Sildenafil; Sildenafil Citrate - pharmacology; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2015-4252

Context:Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients.Objective: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).Design:Randomized, double-blind, placebo-controlled study in type 2 diabetes.Patients and Intervention: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.Main Outcomes and Measures:Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT.Results: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.Conclusions:Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.