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Inhibition of P2X7 Purinergic Receptor Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1? Pathway.

ABSTRACT: P2X7 purinergic receptor (P2X7R) has been implicated in several cardiovascular diseases. However, whether it regulates cardiac fibrosis remains elusive. Herein, its involvement in the development of cardiac fibrosis was examined using a transverse aortic constriction (TAC) mice model and cardiac fibroblasts (CFs) hyperstimulated by TGF-?1 for 48 hours. Results showed that TAC and TGF-?1 treatment increased the expression of P2X7R. Silencing of P2X7R expression with siP2X7R ameliorated TGF-?1 effects on fibroblasts activation. Similarly, P2X7R inhibition by Brilliant Blue G (BBG) reduced mRNA and protein levels of profibrosis markers, while the P2X7R agonist BzATP accelerated the TGF-?1-induced CFs activation. Moreover, it was found that TGF-?1-induced CFs activation was mediated by the NLRP3/IL-1? inflammasome pathway. BBG or siP2X7R treatment suppressed NLRP3/IL-1? pathway signaling. In vivo, BBG significantly alleviated TAC-induced cardiac fibrosis, cardiac dysfunction, and NLRP3/IL-1? activation. Collectively, our findings imply that suppressing P2X7R may limit cardiac fibrosis and abnormal activation of CFs.

SUBMITTER: Zhou J

PROVIDER: S-EPMC7261319 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inhibition of P2X7 Purinergic Receptor Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1β Pathway.

Zhou Junteng J Tian Geer G Quan Yue Y Li Junli J Wang Xiaojiao X Wu Wenchao W Li Miaoling M Liu Xiaojing X

Oxidative medicine and cellular longevity 20200521

P2X7 purinergic receptor (P2X7R) has been implicated in several cardiovascular diseases. However, whether it regulates cardiac fibrosis remains elusive. Herein, its involvement in the development of cardiac fibrosis was examined using a transverse aortic constriction (TAC) mice model and cardiac fibroblasts (CFs) hyperstimulated by TGF-β1 for 48 hours. Results showed that TAC and TGF-β1 treatment increased the expression of P2X7R. Silencing of P2X7R expression with siP2X7R ameliora ...[more]

PMID: 32566102

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Project description:Background:High-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. Methods:Three 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 ?M 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-1? in serum or supernatants were measured by ELISA. Results:In 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-?. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1? 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-1? of H9c2 cells, inhibited collagen I, TGF-?, 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. Conclusion:Aerobic 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.

Dataset Information

Inhibition of P2X7 Purinergic Receptor Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1? Pathway.

Publications

Inhibition of P2X7 Purinergic Receptor Ameliorates Cardiac Fibrosis by Suppressing NLRP3/IL-1<i>β</i> Pathway.

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