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.
J Clin Endocrinol Metab. 2016 Apr;101(4):1525-34. doi: 10.1210/jc.2015-4252. Epub 2016 Mar 10.
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.
内脏脂肪在心血管风险中起着重要作用。PDE5 抑制剂（PDE5i）可改善 2 型糖尿病患者的心脏功能和胰岛素敏感性。
通过基于药理学调节 microRNA（miRNA）的微阵列分析，研究 PDE5i 是否影响内脏脂肪组织（VAT），特别是心外膜脂肪（心外膜脂肪组织[EAT]），以及涉及哪些机制。
2 型糖尿病的随机、双盲、安慰剂对照研究。
共有 59 名糖尿病患者被随机分为接受 100mg/d 西地那非或安慰剂治疗 12 周。在患者的亚组中采集脂肪活检。在平行方案中，db/db 小鼠随机接受 12 周的西地那非或载体治疗，并采集 VAT。
人体测量和代谢参数，通过心脏磁共振成像量化 EAT，2005 种循环 miRNA 的阵列，定量 PCR，以及 VAT 的流式细胞术。
与安慰剂相比，西地那非降低了腰围（P =.024）和 EAT（P =.045）。微阵列分析确定了一些由西地那非差异调节的 miRNA，包括 miR-22-3p 的下调，通过实时定量 PCR 证实（P <.001）。在 HL1 心肌细胞中证实了西地那非对 miR-22-3p 表达的调节。在接受西地那非治疗的患者的血清和皮下脂肪中均发现了已知的 miR-22-3p 靶标 SIRT1 的上调。与载体相比，12 周的西地那非治疗下调了 db/db 小鼠 VAT 中的 miR-22-3p，并上调了 Sirtuin1（SIRT1）基因表达，使脂肪组织细胞组成向炎症程度较低的方向转变。
在人类和糖尿病小鼠模型中，PDE5i 的治疗可改善 VAT，通过调节 miR-22-3p 表达靶向 SIRT1。
