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PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial
Daniela Fiore1, Daniele Gianfrilli1, Elisa Giannetta1
1Department 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.
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 Outcome 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.
Insights
Phosphodiesterase type 5 inhibitors (PDE5i) like sildenafil can reduce visceral fat, including epicardial fat, in type 2 diabetes patients. This occurs by modulating miR-22-3p to increase SIRT1 expression, improving adipose tissue inflammation.
Area of Science:
- Cardiovascular Research
- Metabolic Disease Research
- Pharmacology
Background:
- Visceral adiposity is a key contributor to cardiovascular risk.
- Phosphodiesterase type 5 inhibitors (PDE5i) show potential in improving cardiac function and insulin sensitivity in type 2 diabetes.
Purpose of the Study:
- To determine if PDE5i impact visceral adipose tissue (VAT), specifically epicardial adipose tissue (EAT).
- To elucidate the underlying mechanisms involving microRNA (miRNA) modulation.
Main Methods:
- A randomized, double-blind, placebo-controlled study involving 59 type 2 diabetes patients treated with sildenafil or placebo for 12 weeks.
- Microarray profiling of miRNAs, quantitative PCR, and flow cytometry were used on fat biopsies and in a murine model (db/db mice).
Main Results:
- Sildenafil significantly reduced waist circumference and EAT compared to placebo.
- Microarray analysis revealed sildenafil down-regulated miR-22-3p and up-regulated SIRT1 in both human subjects and mice.
- These changes were associated with a shift in adipose tissue toward a less inflamed profile.
Conclusions:
- PDE5 inhibitors effectively improve VAT and EAT in diabetic patients and models.
- The mechanism involves targeting SIRT1 through the modulation of miR-22-3p expression.
- This suggests a novel therapeutic strategy for managing metabolic and cardiovascular risks associated with visceral adiposity.
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