Cytoplasmic translocation of HuR contributes to angiotensin II induced cardiac fibrosis

Bai, Danna; Ge, Lan; Gao, Yan; Lü, Xin; Wang, Haichang; Yang, Guodong

doi:10.1016/j.bbrc.2015.06.101

Cited by 12 publications

(7 citation statements)

References 20 publications

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“…The cytotoxic effect of Epi was partly mediated by the generation of ROS that subsequently damage mitochondria leading to apoptosis [ 21 , 27 ]. It has also been reported that ROS generation triggered cytoplasmic translocation of HuR, leading to enhancement in activity of TGFβ pathway (ROS-HuR-TGFβ pathway) [ 28 ]. Moreover, HuR was implicated in posttranscriptional regulation of NADPH oxidase-1 (NOX-1), one crucial enzyme for ROS production [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells

et al. 2017

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HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/β-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., β-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, β-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, ß-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/β-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells.

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Section: Resultsmentioning

confidence: 99%

Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells

et al. 2017

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“…Other mechanisms besides activation of redox-sensitive transcription factors may explain the relationship between ANG II-induced Nox2/4 activity and cardiac fibrosis. For example, ANG II-induced collagen production is linked to ROS-induced activation of the RNA binding protein HuR and stabilization of TGF-␤ mRNA in mouse cardiac fibroblasts (47). Also, mitochondria may constitute an additional source of ROS for driving fibrosis.…”

Section: Egfr Nox and Rosmentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

812

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…The renin/angiotensin/aldosterone system plays an important role in normal myocardial function. However, chronic elevation in angiotensin II (Ang II) levels is associated with fibrosis among other pathological remodeling adverse effects [20]. TGFβ activation occurs downstream Ang II activity and implicates TGFβ-dependent collagen synthesis [21].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein

Cáceres

Chavez

Maestro

et al. 2018

Journal of Molecular and Cellular Cardiology

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Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFβ-Smad2/3 signaling. Targeting the ubiquitous TGFβ leads to cellular homeostasis deregulation with adverse consequences. We previously showed the anti-fibrotic effects upon downregulation of 90-kDa heat shock protein (Hsp90), a chaperone that associates to the TGFβ signaling cascade. In the present study, we use a fluorescent-labeled Hsp90 protein inhibitor (CTPR390-488) with specific Hsp90 binding properties to reduce myocardial pro-fibrotic events in vitro and in vivo. The mechanism of action involves the disruption of TGFβRI-Hsp90 complex, resulting in a decrease in TGFβ signaling and reduction in extracellular matrix collagen. In vivo, decreased myocardial collagen deposition was observed upon CTPR390-488 treatment in a pro-fibrotic mouse model. This is the first study demonstrating the ability of an engineered Hsp90 protein inhibitor to block collagen expression, reduce the motility of myocardial TGFβ-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.

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Cytoplasmic translocation of HuR contributes to angiotensin II induced cardiac fibrosis

Cited by 12 publications

References 20 publications

Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells

Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein

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