P2X7 receptor regulates EMMPRIN and MMP‑9 expression through AMPK/MAPK signaling in PMA‑induced macrophages

Lü, Lin; Huang, Shenghui; Zhu, Zhouyang; Han, Jibo; Wang, Zhengxian; Huang, Weijian; Huang, Zhouqing

doi:10.3892/mmr.2018.9282

Cited by 12 publications

(11 citation statements)

References 38 publications

(41 reference statements)

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“…Consequently, inhibiting EMMPRIN and MMP-9 levels can be beneficial for the stability of atherosclerotic plaques. Notably, we previously revealed that P2X7R effectively regulates both EMMPRIN and MMP-9 during monocyte differentiation into macrophages (Lin et al, 2018). In this study, we demonstrated that P2X7R was upregulated under oxLDL stimulation in macrophages and that its inhibition significantly reduced EMMPRIN and MMP-9 expression, which indicates that P2X7R is a regulator of EMMPRIN and MMP-9 and could be a potential therapeutic target for inhibiting plaque rupture or retarding atherosclerosis.…”

Section: Discussionmentioning

confidence: 51%

Berberine Regulated miR150-5p to Inhibit P2X7 Receptor, EMMPRIN and MMP-9 Expression in oxLDL Induced Macrophages

et al. 2021

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Elevated extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 (MMP-9) in oxidized low density lipoprotein (oxLDL)-induced macrophages leads to the progression of vulnerable plaques by degradation of the extracellular matrix. Our previous report showed that berberine regulates the expression of both EMMPRIN and MMP-9. In addition, P2X7 receptor (P2X7R) upregulation plays a crucial role in the development of atherosclerosis. However, it is unclear whether berberine regulated P2X7R level to inhibit both EMMPRIN and MMP-9 expession in macrophages. In the present study, we investigated the impact of berberine on P2X7R expression and the regulation of P2X7R in the expression of EMMPRIN and MMP-9 in oxLDL-induced macrophages. We found that P2X7R expression was increased, miR150-5p was reduced in oxLDL-induced macrophages, relatively. And A-438079 (a P2X7R inhibitor) or miR150-5p mimic treatment greatly reversed the upregulation of EMMPRIN and MMP-9 expression. Moreover, A-438079 significantly reduced oxLDL-induced AMP-activated protein kinase-α (AMPK-α) phosphorylation and reversed the activation of mitogen-activated protein kinase (MAPK), which in turn decreased the expression of EMMPRIN and MMP-9. These findings illustrate that P2X7R suppresses EMMPRIN and MMP-9 expression by inhibiting the AMPK-α/MAPK pathway in oxLDL-induced macrophages. Accordingly, exposure to berberine markedly upregulated miR150-5p, decreased P2X7R expression and downregulated MMP-9 and EMMPRIN levels in oxLDL-induced macrophages, resulting in AMPK-α/MAPK (JNK, p38, and ERK) inactivation. Overall, these results indicate that berberine increased miR150-5p level, subsequently inhibits P2X7R-mediated EMMPRIN and MMP-9 expression by suppressing AMPK-α and MAPK signaling in oxLDL-induced macrophages.

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Section: Discussionmentioning

confidence: 51%

Berberine Regulated miR150-5p to Inhibit P2X7 Receptor, EMMPRIN and MMP-9 Expression in oxLDL Induced Macrophages

et al. 2021

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“…Also, knocking out P2X7R inhibits pulmonary fibrosis (Liu et al, 2015), and P2X7R levels contributes to the release of MMP9, an important mediator of myocardial remodeling (Riteau et al, 2010). And our previous research showed that the inhibition of P2X7R downregulated both EMMPRIN and MMP9 expression (Gu and Wiley, 2006; Yabluchanskiy et al, 2013), and reduced NLRP3 inflammasome activation in PMA-induced macrophages (Lin et al, 2018). Intriguingly, inflammatory factors such as TNF-α induce MMP9 activity (Kong et al, 2016), which promote the activation of TGF-β that subsequently enhances the synthesis of collagen I and deregulates collagen turnover, resulting in the development of fibrosis in the heart.…”

Section: Discussionmentioning

confidence: 98%

Aerobic Exercise Ameliorates Myocardial Inflammation, Fibrosis and Apoptosis in High-Fat-Diet Rats by Inhibiting P2X7 Purinergic Receptors

Chen

Wang

et al. 2019

Front. Physiol.

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BackgroundHigh-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified.MethodsThree groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA.ResultsIn vivo, collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. In vitro, we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited.ConclusionAerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes.

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“…Panx1 was also involved in regulating ATP release, which can activate apoptosis or autophagy signaling (17,18). Extracellular ATP can act as a paracrine molecule to activate P2X7R, which can regulate various signaling pathways, such as the AMPK and MAPK signaling pathway (43). Previous studies have shown that ferroptosis could activate the MAPK pathway through MEK (20).…”

Section: Panx1 Mediates Ferroptosis In Iri-akimentioning

confidence: 99%

Pannexin 1 mediates ferroptosis that contributes to renal ischemia/reperfusion injury

Jiang

Yang

et al. 2019

Journal of Biological Chemistry

146

107

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Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been evaluated widely. Pannexin 1 (PANX1), an ATP-releasing pathway family protein, has pro-apoptotic effects during kidney injury. Here, we demonstrate that PANX1 deletion protects against renal IRI by regulating ferroptotic cell death. Panx1 knockout mice subjected to renal IRI had decreased plasma creatinine, malondialdehyde (MDA) levels in kidney tissues, and tubular cell death (visible as decreased TUNEL-positive renal tubular cells) compared with WT mice. In cultured human kidney 2 (HK-2) cells, silenced Panx1 expression significantly attenuated ferroptotic lipid peroxidation and iron accumulation induced by the ferroptosis inducer erastin. Moreover, the Panx1 silencing significantly modulated ferroptosis-related protein expression. Furthermore, Panx1 deletion induced the expression of a cytoprotective chaperone, heme oxygenase-1 (HO-1), and inhibited ferroptinophagy via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In summary, Panx1 deletion protects against renal IRI by attenuating MAPK/ERK activation in a ferroptotic pathway. Our findings provide critical insights into the role of PANX1 in ferroptotic cell death and highlight a potential therapeutic target for the management of acute kidney injury (AKI) during the perioperative period.Acute kidney injury (AKI) 2 is a frequent complication after cardiac surgery, which contributes to increased mortality, and

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P2X7 receptor regulates EMMPRIN and MMP‑9 expression through AMPK/MAPK signaling in PMA‑induced macrophages

Cited by 12 publications

References 38 publications

Berberine Regulated miR150-5p to Inhibit P2X7 Receptor, EMMPRIN and MMP-9 Expression in oxLDL Induced Macrophages

Berberine Regulated miR150-5p to Inhibit P2X7 Receptor, EMMPRIN and MMP-9 Expression in oxLDL Induced Macrophages

Aerobic Exercise Ameliorates Myocardial Inflammation, Fibrosis and Apoptosis in High-Fat-Diet Rats by Inhibiting P2X7 Purinergic Receptors

Pannexin 1 mediates ferroptosis that contributes to renal ischemia/reperfusion injury

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