MiR-21-3p Inhibits Adipose Browning by Targeting FGFR1 and Aggravates Atrial Fibrosis in Diabetes.

Jian-An Pan,Chang-Qian Wang,Hao Lin,Jun Gu,Hui-Li Zhang,Jian-Ying Yu,Jun-Feng Zhang,Antonio Desmond Mccarthy

doi:10.1155/2021/9987219

Jian-An Pan, Chang-Qian Wang + Show 6 more

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https://doi.org/10.1155/2021/9987219

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Abstract

A relationship between excess epicardial adipose tissue (EAT) and the risk of atrial fibrillation (AF) has been reported. Browning of EAT may be a novel approach for the prevention or treatment of AF by attenuating atrial fibrosis. Previous studies have identified microRNA-21 (miR-21) as a regulatory factor in atrial fibrosis. The present study examined the role of different subtypes of miR-21 in adipose browning and atrial fibrosis under hyperglycemic conditions. Wild type and miR-21 knockout C57BL/6 mice were used to establish a diabetic model via intraperitoneal injection of streptozotocin. A coculture model of atrial fibroblasts and adipocytes was also established. We identified miR-21-3p as a key regulator that controls adipocyte browning and participates in atrial fibrosis under hyperglycemic conditions. Moreover, fibroblast growth factor receptor (FGFR) 1, a direct target of miR-21-3p, decreased in this setting and controlled adipose browning. Gain and loss-of-function experiments identified a regulatory pathway in adipocytes involving miR-21a-3p, FGFR1, FGF21, and PPARγ that regulated adipocyte browning and participated in hyperglycemia-induced atrial fibrosis. Modulation of this signaling pathway may provide a therapeutic option for the prevention and treatment of atrial fibrosis or AF in DM.

Highlights

Despite many available treatments, diabetes mellitus (DM) remains a major public health problem that currently affects more than 425 million people worldwide [1]
We examined inflammatory factors in coculture supernatants, including TNFα, interleukin 6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1), and found that these inflammatory factors were markedly increased by transfection with miR-21-3p mimics in adipocytes compared with cells transfected with mimics negative control (NC) or miR-21-5p mimics under both low glucose (LG) and high glucose (HG) conditions (Figure 3(c))
The results showed that miR-213p efficiently suppressed uncoupling protein-1 (UCP-1) expression in adipocytes by inhibiting FGFR1 via the FGFR1/Fibroblast growth factor 21 (FGF21)/PPARγ pathway, which was partially reversed by upregulation of FGFR1 via pcDNA-FGFR1 transfection (Figures 4(h)–4(j))

Summary

Introduction

Diabetes mellitus (DM) remains a major public health problem that currently affects more than 425 million people worldwide [1]. The role of adipose browning in DM-induced atrial fibrosis remains to be elucidated. The biological roles of FGF21 are affected via downstream signaling pathways by binding to fibroblast growth factor receptors (FGFRs) and proliferator-activated receptor gamma (PPARγ) activation [16]. MiR-21 was previously shown to be associated with atrial fibrosis [18,19,20], but most of its mechanisms have focused on cardiomyocyte damage and fibroblast activation. We identified miR-21-3p (a subtype of the miR-21 family) as a key regulator that controls adipose browning and participates in atrial fibrosis under hyperglycemic conditions. FGFR1 (a direct target of miR-21-3p) is decreased in these conditions and controls WAT to BAT differentiation via the FGFR1/FGF21/PPARγ pathway

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Conflicts of Interest