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 2016-04, Vol.101 (4), p.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: Article
• Language: English
• Subjects: Adiposity - drug effects; Adiposity - genetics; Adult; Aged; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry; Diabetes Mellitus, Type 2 - physiopathology; Double-Blind Method; Flow Cytometry; Humans; Male; Mice; Mice, Obese; MicroRNAs - genetics; Middle Aged; Obesity, Abdominal - drug therapy; Obesity, Abdominal - metabolism; Obesity, Abdominal - pathology; Phosphodiesterase 5 Inhibitors - pharmacology; Real-Time Polymerase Chain Reaction; Sildenafil Citrate - pharmacology; Sirtuin 1 - genetics; Sirtuin 1 - metabolism
• ISSN: 0021-972X; 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. This trial provides in-vivo and in-vitro evidence that chronic inhibition of PDE5 in type 2 diabetes regulates miR22 release, SIRT1 expression and epicardial fat, thus improving cardiovascular risk.