PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial
PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial
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DOI：
10.1210/jc.2015-4252
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发表时间：
2016-04-01
影响因子：
5.8
通讯作者：
Isidori, Andrea M.
中科院分区：
文献类型：
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作者：
Fiore, Daniela;Gianfrilli, Daniele;Isidori, Andrea M.
背景：内脏肥胖在心血管风险中起着重要作用。目的：探讨PDE 5i对2型糖尿病患者内脏脂肪组织（VAT），特别是心外膜脂肪的影响（心外膜脂肪组织[EAT]），以及所涉及的机制，使用基于微阵列的药理学调节微小RNA（miRNA）分析。设计：2型糖尿病的随机、双盲、安慰剂对照研究患者和干预：共有59名糖尿病患者随机接受100 mg/d西地那非或安慰剂治疗12周。在一个亚组的患者中收集脂肪活检。在平行方案中，db/db小鼠被随机分配至12周的西地那非或载体，并且收集VAT.Main Outcomes and Measures：人体测量和代谢参数，通过心脏磁共振成像的EAT定量，2005个循环miRNAs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 = 0.024）和EAT（P = 0.045）。微阵列分析鉴定了西地那非差异调节的一些miRNAs，包括下调miR-22- 3 p，通过实时定量PCR证实（P < .001）。西地那非对miR-22- 3 p表达的调节在体外HL 1心肌细胞中得到证实。SIRT 1是miR-22- 3 p的已知靶点，在西地那非治疗受试者的血清和皮下脂肪中均发现了SIRT 1的上调。与载体相比，12周的西地那非治疗下调miR-22- 3 p和上调SIRT 1（SIRT 1）基因表达的增值税从db/db小鼠，脂肪组织细胞组成向一个较小的发炎profile.Conclusions：治疗与PDE 5i在人类和小鼠糖尿病模型改善增值税，通过调节miR-22- 3 p的表达，靶向SIRT 1。
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.