Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart

Rawal, Shruti; Munasinghe, Pujika Emani; Nagesh, Prashanth Thevkar; Lew, Jason Kar Sheng; Jones, Gregory T.; Williams, Michael J.A.; Davis, Philip J.; Bunton, Dick; Galvin, Ivor F.; Manning, Patrick J.; Lamberts, Regis R.; Katare, Rajesh

doi:10.1042/cs20160916

Cited by 67 publications

(64 citation statements)

References 41 publications

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“…Moreover, several other miRNAs that were in higher abundance in CMC db/db -derived EVs have been shown to have beneficial actions. For example, the levels of miR-15a, mi339–5p, and mi-370 were higher in EVs derived from CMC db/db cells, and these are thought to be involved in tissue regeneration or fibrosis [37, 51, 53]. That these in vitro measures of cell competence do not equate to in vivo efficacy is an important outcome of this study that merits further investigation.…”

Section: Discussionmentioning

confidence: 97%

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

et al. 2018

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Although cell therapy improves cardiac function after myocardial infarction, highly variable results and limited understanding of the underlying mechanisms preclude its clinical translation. Because many heart failure patients are diabetic, we examined how diabetic conditions affect the characteristics of cardiac mesenchymal cells (CMC) and their ability to promote myocardial repair in mice. To examine how diabetes affects CMC function, we isolated CMCs from non-diabetic C57BL/6J (CMCWT) or diabetic B6.BKS(D)-Leprdb/J (CMCdb/db) mice. When CMCs were grown in 17.5 mM glucose, CMCdb/db cells showed > twofold higher glycolytic activity and a threefold higher expression of Pfkfb3 compared with CMCWT cells; however, culture of CMCdb/db cells in 5.5 mM glucose led to metabolic remodeling characterized by normalization of metabolism, a higher NAD+/NADH ratio, and a sixfold upregulation of Sirt1. These changes were associated with altered extracellular vesicle miRNA content as well as proliferation and cytotoxicity parameters comparable to CMCWT cells. To test whether this metabolic improvement of CMCdb/db cells renders them suitable for cell therapy, we cultured CMCWT or CMCdb/db cells in 5.5 mM glucose and then injected them into infarcted hearts of non-diabetic mice (CMCWT, n = 17; CMCdb/db, n = 13; Veh, n = 14). Hemodynamic measurements performed 35 days after transplantation showed that, despite normalization of their properties in vitro, and unlike CMCWT cells, CMCdb/db cells did not improve load-dependent and -independent parameters of left ventricular function. These results suggest that diabetes adversely affects the reparative capacity of CMCs and that modulating CMC characteristics via culture in lower glucose does not render them efficacious for cell therapy.

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Section: Discussionmentioning

confidence: 97%

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

et al. 2018

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“…Extensive atrial brosis resulting from hyperglycemia is thought to play a key role in both initiating and perpetuation AF as an increase of collagen deposition in the atria can cause abnormal conduction of signals, rupture of the propagating waves, and even the occurrence of re-entry 30 . In diabetic conditions, broblasts are activated leading to inappropriate collagen production and deposition no matter in type I DM 31,32 or type II DM [33][34][35] . Emerging evidence poses a unique challenge to understanding the pathogenesis of atrial brillation caused by diabetes, which is often consistent with obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicated that miRs function as important regulators that participates in DM-induced atrial brosis 35 . The role of miR-21 in the pathogenesis of atrial brosis has been illuminated, and increased miR-21 expression was correlated positively with atrial brosis or brotic gene expression [20][21][22] signaling pathway by decrease CADM1 expression 58 .…”

Section: Discussionmentioning

confidence: 99%

MiR-21-3p regulation FGFR1/FGF21/PPARγ pathway induces atrial fibrosis by targeting FGFR1 in diabetes

Pan¹,

Lin

et al. 2020

Preprint

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Background: A relationship between the abundance of epicardial adipose tissue (EAT) and the risk of atrial fibrosis and atrial fibrillation (AF) in diabetes mellitus (DM) has been reported. And previous studies have shown that MicroRNA-21 (miR-21) is a regulatory factor in atrial fibrosis and AF. The aim of this study was to examine the role of different subtypes of miR-21 in EAT browning and atrial fibrosis under hyperglycemia conditions.Methods: In vivo, C57BL/6 wild type (WT) and miR-21 knockout (KO) mice were used to establish the diabetic model by intraperitoneal injection of streptozotocin (STZ). In vitro, the EAT adipocytes from miR-21 KO mice were cultured and transfected with miR-21-3p mimic or miR-21-5p mimic and co-cultured with atrial fibroblasts in both HG or LG conditions. The browning of EAT and the fibrosis of fibroblasts were assessed by western blotting, immunofluorescence, Masson staining, and ELISA. The gain- and loss-of-function experiments were used to identified fibroblast growth factor receptor 1 (FGFR1) as the target gene of miR-21-3p.Results: In patients with DM and/or AF, serum hsa-miR-21-3p, instead of hsa-miR-21-5p, was significantly up-regulated. And miR-21 KO clearly ameliorated the atrial fibrosis in the diabetic mice. miR-21-3p as a key regulator that controls EAT browning and participates in atrial fibrosis under hyperglycemia conditions. Moreover, our gain- and loss-of-function experiments showed that FGFR1, as a direct target of miR-21-3p identified a regulatory pathway in EAT adipocytes. Conclusions: MiR-21-3p regulated EAT browning and participated the process of hyperglycemia-induced atrial fibrosis by targeting FGFR1.

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“…Extensive atrial fibrosis resulting from hyperglycemia is thought to play a key role in both initiating and perpetuation AF as an increase of collagen deposition in the atria can cause abnormal conduction of signals, rupture of the propagating waves, and even the occurrence of re-entry [30]. In diabetic conditions, fibroblasts are activated leading to inappropriate collagen production and deposition no matter in type I DM [31,32] or type II DM [33][34][35]. Emerging evidence poses a unique challenge to understanding the pathogenesis of atrial fibrillation caused by diabetes, which is often consistent with obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicated that miRs function as important regulators that participates in DM-induced atrial fibrosis [35]. The role of miR-21 in the pathogenesis of atrial fibrosis has been illuminated, and [59,60].…”

Section: Discussionmentioning

confidence: 99%

MiR-21-3p regulation FGFR1/FGF21/PPARγ pathway induces atrial fibrosis by targeting FGFR1 in diabetes

Pan

et al. 2020

Preprint

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Background A relationship between the abundance of epicardial adipose tissue (EAT) and the risk of atrial fibrillation (AF) in diabetes mellitus (DM) has been reported. And browning of EAT might be a novel approach for prevention or treatment in AF by adjusting atrial fibrosis. MicroRNA-21 (miR-21) is one of the most important miRs, and previous studies have shown that it is a regulatory factor in atrial fibrosis and AF. The aim of this study was to examine the role of different subtypes of miR-21 in EAT browning and atrial fibrosis under hyperglycemia conditions. Methods The expression of serum hsa-miR-21-3p and hsa-miR-21-5p in patients with DM and/or AF were determined by quantitative reverse transcription-polymerase chain reaction. And normal C57BL/6 wild type (WT) and miR-21 knockout (KO) mice were used to establish the diabetic model by intraperitoneal injection of streptozotocin (STZ). In vitro, The EAT adipocytes from miR-21 KO mice were cultured and transfected with miR-21-3p mimic or miR-21-5p mimic and co-cultured with atrial fibroblasts in both HG or LG conditions. The browning of EAT and the fibrosis of fibroblasts were assessed by western blotting, immunofluorescence, Masson staining, and ELISA. Finally, the gain- and loss-of-function experiments were used to identified fibroblast growth factor receptor 1 (FGFR1) as the target gene of miR-21-3p, and the regulatory pathway of miR-21-3p FGFR1, fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptor gamma (PPARγ) that controlled EAT browning and participates the process of hyperglycemia-induced atrial fibrosis. Results In patients with DM and/or AF, serum hsa-miR-21-3p, instead of hsa-miR-21-5p, was significantly up-regulated. And miR-21 KO clearly ameliorated the atrial fibrosis in the diabetic mice. miR-21-3p as a key regulator that controls EAT browning and participates in atrial fibrosis under hyperglycemia conditions. Moreover, our gain- and loss-of-function experiments showed that FGFR1, as a direct target of miR-21-3p identified a regulatory pathway in EAT adipocytes consisting of miR-21-3p, FGFR1, FGF21 and PPARγ. Conclusions MiR-21-3p regulated EAT browning and participates the process of hyperglycemia-induced atrial fibrosis by targeting FGFR1/FGF21/PPARγ pathway.

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Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart

Cited by 67 publications

References 41 publications

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair

MiR-21-3p regulation FGFR1/FGF21/PPARγ pathway induces atrial fibrosis by targeting FGFR1 in diabetes

MiR-21-3p regulation FGFR1/FGF21/PPARγ pathway induces atrial fibrosis by targeting FGFR1 in diabetes

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