Upregulation of Nox4 Promotes Angiotensin II-Induced Epidermal Growth Factor Receptor Activation and Subsequent Cardiac Hypertrophy by Increasing ADAM17 Expression

Zeng, Sha; Chen, Xi; Li, Qin; Wang, Yuhua; Zou, Jian; Cao, Weiwei; Luo, Jiani; Gao, Hui; Liu, Pei-Qing

doi:10.1016/j.cjca.2013.04.026

Cited by 28 publications

(34 citation statements)

References 20 publications

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“…6). Consistent with previous reports, [25][26][27] our experiments have demonstrated that NOX4 is upregulated by various vasoactive agonists such as AngII and ISO, and in response to pressure overload. However, some data from mice with NOX4 transgene have shown that overexpression of NOX4 directly cause cell apoptosis without significant hypertrophy, 28,29 The possible reason for this disparity between our data and theirs might be explained by the different amount of NOX4 expression.…”

Section: Discussionsupporting

confidence: 81%

Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1

Chen

Zhao

et al. 2017

Cell Cycle

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NADPH oxidase 4 (NOX4) and the NOX4-related redox signaling are implicated in cardiac hypertrophy. NOX4 is interrelated with endoplasmic reticulum stress (ERS). Spliced X-box binding protein 1 (Xbp1s) is a key mediator of ERS while its role in cardiac hypertrophy is still poorly understood. Recently, receptor interacting protein kinase 1(RIPK1) has been increasingly reported to be associated with ERS. Therefore, we aimed to test the hypothesis that Xbp1s mediates NOX4-triggered cardiac hypertrophy via RIPK1 signaling. In the heart tissue of transverse aortic constriction (TAC) rats and in primary cultured neonatal cardiomyocytes(NCMs) treated with angiotensinII(AngII) or isoproterenol (ISO), NOX4 expression and reactive oxygen species (ROS) generation, and expression of Xbp1s as well as RIPK1-related phosphorylation of P65 subunit of NF-kB were elevated. Gene silencing of NOX4 by specific small interfering RNA (siRNA) significantly blocked the upregulation of NOX4, generation of ROS, splicing of Xbp1 and activation of the RIPK1-related NF-kB signaling, meanwhile attenuated cardiomyocyte hypertrophy. In addition, ROS scavenger (N-acetyl-L-cysteine, NAC) and NOX4 inhibitor GKT137831 reduced ROS generation and alleviated activation of Xbp1 and RIPK1-related NF-kB signaling. Furthermore, splicing of Xbp1 was responsible for the increase in RIPK1 expression in AngII or ISO-treated NCMs. Upregulated RIPK1 in turn activates NF-kB signaling in a kinase activity-independent manner. These findings suggest that Xbp1s plays an important role in NOX4-triggered cardiomyocyte hypertrophy via activating its downstream effector RIPK1, which may prove significant for the development of future therapeutic strategies. KEYWORDS cardiac hypertrophy; endoplasmic reticulum stress; NADPH oxidase 4; receptor interacting protein kinase 1; X-box binding protein 1

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Section: Discussionsupporting

confidence: 81%

Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1

Chen

Zhao

et al. 2017

Cell Cycle

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“…NOX4-derived ROS can also inactivate PTEN [16,29], which is a well-known negative regulator of PI3K/Akt activity. Besides, NOX4 has been shown to promote the phosphorylation of EGFR [30,31], whose activation results in stimulation of PI3K/Akt pathway, and this effect may be, at least partly dependent on redox regulation of PTP1B [32]. These findings suggest that the mechanisms for NOX4-stimulated PI3K/Akt pathway are complicated and there may be crosstalk with other signals, like EGFR signaling, to further activate PI3K/Akt signaling.…”

Section: Discussionmentioning

confidence: 99%

NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling

et al. 2014

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NADPH oxidase 4 (NOX4) is deregulated in various cancers and involved in cancer proliferation and metastasis. However, what the role of NOX4 plays during malignant progression of non-small cell lung cancer (NSCLC) remains unknown. Our results show that NOX4 was upregulated in NSCLC cell lines and samples from patients, compared with controls; NOX4 protein levels were closely correlated with clinical disease stage and survival time. Overexpression of NOX4 in A549 and H460 NSCLC cells enhanced cell proliferation and invasion in vitro, and produced larger tumors, shorter survival time, and more lung metastasis in nude mice than control cells. On the contrary, NOX4 depletion inhibited NSCLC cell aggressiveness. Inhibition of PI3K/Akt pathway could sufficiently block the cellular effects of NOX4 overexpression in NSCLC cells both in vitro and in vivo. Specifically, we demonstrated that PI3K/Akt pathway also positively regulated NOX4 expression via NF-κB-mediated manner. Therefore, there existed a mutual positive regulation between NOX4 and PI3K/Akt signaling in NSCLC cells, and NOX4 was confirmed to functionally interplay with PI3K/Akt signaling to promote NSCLC cell proliferation and invasion. In conclusion, the positive feedback loop between NOX4 and PI3K/Akt signaling contributes to NSCLC progression.

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“…EGFR transactivation also elicits downstream ER stress leading to cardiac hypertrophy and fibrosis (465,1035). In vitro analysis indicates ANG II-induced EGFR transactivation is dependent on Nox2/Nox4-mediated upregulation of ADAM17 (1236). Knockdown of ADAM17 with siRNA attenuated cardiac hypertrophy in the spontaneously hypertensive rat without diminishing blood pressure, and cardiac hypertrophy and fibrosis in the mouse with ANG II infusion, although the increase in blood pressure was moderately attenuated (1123).…”

Section: Ang II In Cardiac Hypertrophymentioning

confidence: 99%

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

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

773

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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Upregulation of Nox4 Promotes Angiotensin II-Induced Epidermal Growth Factor Receptor Activation and Subsequent Cardiac Hypertrophy by Increasing ADAM17 Expression

Cited by 28 publications

References 20 publications

Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1

Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1

NOX4 promotes non-small cell lung cancer cell proliferation and metastasis through positive feedback regulation of PI3K/Akt signaling

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

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