MiR-22 Suppresses BMP7 in the Development of Cirrhosis

Park

et al. 2016

Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.

Section: Introductionmentioning

confidence: 99%

TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

Park

et al. 2016

“…MicroRNAs (miRNAs) are small non-coding RNAs that regulate protein translation through their base-pairing with the 3′-untranslated region (3′-UTR) of the target mRNAs [28][29][30][31][32][33][34]. MiRNAs play essential roles in regulating atherosclerosis [5,35,36].…”

Section: Introductionmentioning

confidence: 99%

Endothelial Cell Autophagy in Atherosclerosis is Regulated by miR-30-Mediated Translational Control of ATG6

Zhang

Tian

Wang

et al. 2015

Background/Aims: Endothelial cell injury and subsequent death play an essential role in the pathogenesis of atherosclerosis. Autophagy of endothelial cells has a protective role against development of atherosclerosis, whereas the molecular regulation of endothelial cell autophagy is unclear. MicroRNA-30 (miR-30) is a known autophagy suppressor in some biological processes, while it is unknown whether this regulatory axis may be similarly involved in the development of atherosclerosis. Here, we aimed to answer these questions in the current study. Methods: We examined the levels of endothelial cell autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of autophagy-associated protein 6 (ATG6, or Beclin-1) and the levels of miR-30 in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-30 and 3'-UTR of ATG6 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-30 were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). Results: HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. Compared to NOR mice, HFD mice had significantly lower levels of endothelial cell autophagy, resulting from decreases in ATG6 protein, but not mRNA. The decreases in ATG6 in endothelial cells were due to HFD-induced increases in miR-30, which suppressed the translation of ATG6 mRNA via 3′-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. Conclusion: Upregulation of miR-30 by HFD may impair the protective effects of endothelial cell autophagy against development of atherosclerosis through suppressing protein translation of ATG6.

“…MicroRNAs (miRNAs) are 18-22-nucleotide non-coding RNAs that negatively regulate human genes during physiological and pathophysiological processes, basically through their base-pairing with the 3′-untranslated region (3′-UTR) of target mRNAs [16][17][18][19][20][21][22]. Accumulating evidence has implicated miRNAs as essential regulators of atherosclerosis by targeting key factors in the regulatory pathways [3,23,24].…”

Section: Introductionmentioning

confidence: 99%

Atherosclerosis-Associated Endothelial Cell Apoptosis by MiR-429-Mediated Down Regulation of Bcl-2

Zhang¹,

Tian²,

Wang³

et al. 2015

Background/Aims: Endothelial cell injury and subsequent apoptosis play a key role in the development and pathogenesis of atherosclerosis, which is hallmarked by dysregulated lipid homeostasis, aberrant immunity and inflammation, and plaque-instability-associated coronary occlusion. Nevertheless, our understanding of the mechanisms underlying endothelial cell apoptosis is still limited. MicroRNA-429 (miR-29) is a known cancer suppressor that promotes cancer cell apoptosis. However, it is unknown whether miR-429 may be involved in the development of atherosclerosis through similar mechanisms. We addressed these questions in the current study. Methods: We examined the levels of endothelial cell apoptosis in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of anti-apoptotic protein Bcl-2 and the levels of miR-429 in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-429 and 3'-UTR of Bcl-2 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-429 were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL)-treated human aortic endothelial cells (HAECs). Results: HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. HFD mice had significantly lower percentage of endothelial cells and significantly higher percentage of mesenchymal cells in the aorta than NOR mice. Significantly higher levels of endothelial cell apoptosis were detected in HFD mice, resulting from decreases in Bcl-2 protein, but not mRNA. The decreases in Bcl-2 in endothelial cells were due to increased levels of miR-429, which suppressed the translation of Bcl-2 mRNA via 3'-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. Conclusion: Atherosclerosis-associated endothelial cell apoptosis may result from down regulation of Bcl-2, through increased miR-429 that binds and suppresses translation of Bcl-2 mRNA.