AMPK-independent inhibition of human macrophage ER stress response by AICAR

Boß, Marcel; Newbatt, Yvette; Gupta, Sahil; Collins, Ian; Brüne, Bernhard; Namgaladze, Dmitry

doi:10.1038/srep32111

Cited by 27 publications

(19 citation statements)

References 40 publications

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“…There were several limitations in this investigation. Firstly, all drugs including ACIAR [ 41 , 42 ], Compound C [ 20 , 42 ] and metformin [ 43 ] have off-target effects. Through this investigation, we can only delineate a potential link between the AMPK activation and the retard of aneurysmal growth.…”

Section: Discussionmentioning

confidence: 99%

Effect of AMPK signal pathway on pathogenesis of abdominal aortic aneurysms

et al. 2017

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Background and aimsDetermine the effect of AMPK activation and inhibition on the development of AAA (abdominal aortic aneurysm).MethodsAAA was induced in ApoE−/− mice by Ang II (Angiotensin II)-infusion. AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside) was used as AMPK activator and Compound C was used as AMPK inhibitor. We further investigate the effect of metformin, a widely used anti-diabetic drug which could activate AMPK signal pathway, on the pathogenesis of aneurysm.ResultsPhospho-AMPK level was significantly decreased in AAA tissue compared with control aortas. AICAR significantly reduced the incidence, severity and mortality of aneurysm in the Ang II-infusion model. AICAR also alleviated macrophage infiltration and neovascularity in Ang II infusion model at day 28. The expression of pro-inflammatory factors, angiogenic factors and the activity of MMPs were also alleviated by AICAR during AAA induction. On the other hand, Compound C treatment did not exert obvious protective effect. AMPK activation may inhibit the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription-3 (STAT-3) during AAA induction. Administration of metformin also activated AMPK signal pathway and retarded AAA progression in Ang II infusion model.ConclusionsActivation of AMPK signaling pathway may inhibit the Ang II-induced AAA in mice. Metformin may be a promising approach to the treatment of AAA.

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Section: Discussionmentioning

confidence: 99%

Effect of AMPK signal pathway on pathogenesis of abdominal aortic aneurysms

et al. 2017

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“…The current study shows the ability of AICAR to inhibit TNF-α-induced CFB expression in human RPE cells. Although AICAR is a potent activator of AMPK and many of its effects are mediated by AMPK activation, AMPK-independent effects have also been reported 38 – 42 . In our study, both pharmacologic inhibition and genetic (CRISPR/Cas9) deletion experiments demonstrate that the effects of AICAR on CFB to be ZMP- and AMPK-independent.…”

Section: Discussionmentioning

confidence: 99%

AICAR suppresses TNF-α-induced complement factor B in RPE cells

Chung

Efstathiou

Konstantinou

et al. 2017

Sci Rep

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Age related macular degeneration is the leading cause of blindness in the developed world. Although its precise cause remains elusive, dysfunction of the retinal pigment epithelium (RPE) and dysregulation of complement have been implicated in its pathogenesis. The goal of this study was to evaluate the role of an AMP-dependent kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), on tumor necrosis factor alpha (TNF-α) induction of complement factor B (CFB) in RPE cells. We found that AICAR inhibited TNF-α-induced CFB expression in ARPE-19 and human primary RPE cells in a dose-dependent fashion. Treatment of cells with dipyridamole, which blocks AICAR cellular uptake abolished these effects. In contrast, the adenosine kinase inhibitor, 5-iodotubericidin, which inhibits the conversion of AICAR to the direct activator of AMPK, ZMP, did not reverse the effects on TNF-α-induced CFB expression, suggesting AMPK-independent effects. Indeed, knockout of AMPK in RPE cells using Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 did not abolish the inhibitory effects of AICAR on RPE CFB expression. Collectively, our results suggest that AICAR can suppress TNF-α-induced CFB expression in RPE cells in an AMPK-independent mechanism, and could be used as a therapeutic target in certain complement over-activation scenarios.

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“…The experimental anti-ischemic and anticancer drug AICAR enters the cell through nucleoside transporters ENT1 and CNT3 [87], and, as its 5 -monophosphorylated product ZMP, activates AMPK. AICAR also competes with adenosine in nucleoside transport, which contributes to elevated extracellular adenosine and depression of excitatory synaptic transmission (antagonized by 1 µM cyclopentyltheophylline) in the rat hippocampus [88].…”

Section: Pain Antidepressant Sleep and Other Behavioral Interventionmentioning

confidence: 99%

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

Reitman

2020

Cells

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Many ligands directly target adenosine receptors (ARs). Here we review the effects of noncanonical AR drugs on adenosinergic signaling. Non-AR mechanisms include raising adenosine levels by inhibiting adenosine transport (e.g., ticagrelor, ethanol, and cannabidiol), affecting intracellular metabolic pathways (e.g., methotrexate, nicotinamide riboside, salicylate, and 5-aminoimidazole-4-carboxamide riboside), or undetermined means (e.g., acupuncture). However, other compounds bind ARs in addition to their canonical ‘on-target’ activity (e.g., mefloquine). The strength of experimental support for an adenosine-related role in a drug’s effects varies widely. AR knockout mice are the ‘gold standard’ method for investigating an AR role, but few drugs have been tested on these mice. Given the interest in AR modulation for treatment of cancer, CNS, immune, metabolic, cardiovascular, and musculoskeletal conditions, it is informative to consider AR and non-AR adenosinergic effects of approved drugs and conventional treatments.

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AMPK-independent inhibition of human macrophage ER stress response by AICAR

Cited by 27 publications

References 40 publications

Effect of AMPK signal pathway on pathogenesis of abdominal aortic aneurysms

Effect of AMPK signal pathway on pathogenesis of abdominal aortic aneurysms

AICAR suppresses TNF-α-induced complement factor B in RPE cells

Adenosine-Related Mechanisms in Non-Adenosine Receptor Drugs

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