MicroRNA-9 regulates cardiac fibrosis by targeting PDGFR-β in rats

Wang, Lei; Ma, Likun; Hai, Fan; Yang, Zhe; Li, LongWei; Wang, HanZhang

doi:10.1007/s13105-016-0471-y

Cited by 29 publications

(15 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, miR-9 plays a role in the treatment of cardiac fibrosis. It has been found that miR-9 regulates cardiac fibroblast proliferation and collagen production (32). The present study found that transfection of miR-9 led to an inhibition of cell proliferation in human HSCs (LX-2) as compared to that noted in the control cells.…”

Section: Discussionsupporting

confidence: 47%

MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1

Sun¹,

Zhang²,

Li³

et al. 2017

Oncology Reports

View full text Add to dashboard Cite

Liver fibrosis is a chronic liver disease characterized by the proliferation and activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Research suggests that microRNAs (miRNAs) are a new type of regulator of liver fibrosis. In the present study, we investigated the role of microRNA-9 (miR-9) in the process of liver fibrosis, as well as the underlying mechanism of action. Downregulated levels of miR-9 were found in fibrotic liver tissues and activated HSCs as detected by qRT-PCR; whereas, expression of multidrug resistance‑associated protein 1 (MRP1/ABCC1) was upregulated in the fibrotic liver tissues and activated HSCs. CCK-8 and BrdU assays revealed that miR-9 reduced the proliferative ability of the HSCs. In addition, expression levels of ECM-related genes (α-SMA, Col-1 and Timp-1), which are markers of HSC activation, were downregulated by miR-9. Conversely, an miR-9 inhibitor promoted cell proliferation and HSC activation. In addition, a luciferase reporter assay indicated that miR-9 targets the 3'-untranslated region (3'-UTR) of MRP1 and causes a significant decrease in MRP1. miR-9 inhibited the activation of the Hedgehog (Hh) pathway and the expression of MRP1, while this suppression was rescued by the overexpression of MRP1. Finally, a CCl4-induced mouse model of liver fibrosis was used to investigate the effects of miR-9 on liver fibrosis in vivo. The results showed that miR-9 abrogated hepatic fibrosis by suppressing the expression of MRP1 in CCl4-induced liver fibrotic mice. In conclusion, the present study demonstrated that miR-9 suppresses the proliferation and activation of HSCs through the Hh pathway by targeting MRP1, which suggests that miR-9 has therapeutic potential for liver fibrosis.

show abstract

Section: Discussionsupporting

confidence: 47%

MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1

Sun¹,

Zhang²,

Li³

et al. 2017

Oncology Reports

View full text Add to dashboard Cite

show abstract

“…PDGF growth factors significantly stimulate cardiac fibroblast proliferation in vitro, and neutralization of PDGF receptors alpha and beta reduces collagen deposition in the myocardium in vivo 57 . Additionally, overexpression of PDGFRβ in cardiac fibroblasts leads to enhanced proliferation and collagen synthesis 58,59 . In addition to downregulation of several downstream signaling molecules, such as FAK, p38, and ERK, we found that Sprr3 loss resulted in significantly reduced activation of PDGFRβ following stimulation with PDGFBB, although neither the expression of PDGFRβ nor binding of PDGFBB to its receptors were notably different in Sprr3 deficient cells as compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Small proline‐rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts

Saraswati

Lietman

et al. 2020

FASEB j.

View full text Add to dashboard Cite

Nearly 6 million Americans suffer from heart failure. Increased fibrosis contributes to functional decline of the heart that leads to heart failure. Previously, we identified a mechanosensitive protein, small proline‐rich repeat 3 (SPRR3), in vascular smooth muscle cells of atheromas. In this study, we demonstrate SPRR3 expression in cardiac fibroblasts which is induced in activated fibroblasts following pressure‐induced heart failure. Sprr3 deletion in mice showed preserved cardiac function and reduced interstitial fibrosis in vivo and reduced fibroblast proliferation and collagen expression in vitro. SPRR3 loss resulted in reduced activation of Akt, FAK, ERK, and p38 signaling pathways, which are coordinately regulated by integrins and growth factors. SPRR3 deletion did not impede integrin‐associated functions including cell adhesion, migration, or contraction. SPRR3 loss resulted in reduced activation of PDGFRβ in fibroblasts. This was not due to the reduced PDGFRβ expression levels or decreased binding of the PDGF ligand to PDGFRβ. SPRR3 facilitated the association of integrin β1 with PDGFRβ and subsequently fibroblast proliferation, suggesting a role in PDGFRβ‐Integrin synergy. We postulate that SPRR3 may function as a conduit for the coordinated activation of PDGFRβ by integrin β1, leading to augmentation of fibroblast proliferation and matrix synthesis downstream of biomechanical and growth factor signals.

show abstract

“…In organ fibrosis, miR-9-5p may also act as a negative regulator. For instance, miR-9-5p regulates cardiac fibrosis by targeting PDGFR-β in rats [26]. A recent study has demonstrated that miR-9-5p has a protective role in the fibrogenic transformation of human dermal fibroblasts [27].…”

Section: Discussionmentioning

confidence: 99%

Epigenetically-Regulated MicroRNA-9-5p Suppresses the Activation of Hepatic Stellate Cells via TGFBR1 and TGFBR2

Chen

Fan

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Recently, microRNAs (miRNAs) have been demonstrated to act as regulators of activation of hepatic stellate cells (HSCs). It is well known that the main profibrogenic inducer transforming growth factor-β1 (TGF-β1) contributes to HSC activation, which is a key event in liver fibrosis. Increasing studies show that miR-9-5p is down-regulated in liver fibrosis and restoration of miR-9-5p limits HSC activation. However, the role of miR-9-5p in TGF-β1-induced HSC activation is still not clear. Methods: miR-9-5p expression was quantified using real-time PCR in chronic hepatitis B (CHB) patients and TGF-β1-treated LX-2 cells. In CHB patients, histological activity index (HAI) and fibrosis stages were assessed using the Ishak scoring system. Effects of miR-9-5p on liver fibrosis in vivo and in vitro were analyzed. Luciferase activity assays were performed to examine the binding of miR-9-5p to the 3′-untranslated region of type I TGF-β receptor (TGFBR1) as well as TGFBR2. Results: Compared with healthy controls, miR-9-5p was reduced in CHB patients. There was a lower miR-9-5p expression in CHB patients with higher fibrosis scores or HAI scores. miR-9-5p was down-regulated by TGF-β1 in a dose-dependent manner. TGF-β1-induced HSC activation including cell proliferation, α-SMA and collagen expression was blocked down by miR-9-5p. Notably, miR-9-5p ameliorates carbon tetrachloride-induced liver fibrosis. As determined by luciferase activity assays, TGFBR1 and TGFBR2 were targets of miR-9-5p. Further studies demonstrated that miR-9-5p inhibited TGF-β1/Smads pathway via TGFBR1 and TGFBR2. Interestingly, promoter methylation was responsible for miR-9-5p down-regulation in liver fibrosis. The relationship between miR-9-5p expression and methylation was confirmed in CHB patients and TGF-β1-treated cells. Conclusion: Our results demonstrate that miR-9-5p could inhibit TGF-β1-induced HSC activation through TGFBR1 and TGFBR2. Loss of miR-9-5p is associated with its methylation status in liver fibrosis.

show abstract

MicroRNA-9 regulates cardiac fibrosis by targeting PDGFR-β in rats

Cited by 29 publications

References 21 publications

MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1

MicroRNA-9 limits hepatic fibrosis by suppressing the activation and proliferation of hepatic stellate cells by directly targeting MRP1/ABCC1

Small proline‐rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts

Epigenetically-Regulated MicroRNA-9-5p Suppresses the Activation of Hepatic Stellate Cells via TGFBR1 and TGFBR2

Contact Info

Product

Resources

About