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

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2020 Jun 23

PMID 32566102

Citations 23

Authors

Junteng Zhou

Geer Tian

Yue Quan

Junli Li

Xiaojiao Wang

Wenchao Wu

Miaoling Li

Xiaojing Liu

Affiliations

Soon will be listed here.

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. , 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.

Citing Articles

Exercise in Diabetic Cardiomyopathy: Its Protective Effects and Molecular Mechanism.

Chen H, Guo L Int J Mol Sci. 2025; 26(4).

PMID: 40003929 PMC: 11855851. DOI: 10.3390/ijms26041465.

Inflammasomes and idiopathic inflammatory myopathies.

Sun R, Chu J, Li P Front Immunol. 2024; 15:1449969.

PMID: 39723212 PMC: 11668653. DOI: 10.3389/fimmu.2024.1449969.

P2X receptors exhibit at least three modes of allosteric antagonism.

Oken A, Ditter I, Lisi N, Krishnamurthy I, Godsey M, Mansoor S Sci Adv. 2024; 10(40):eado5084.

PMID: 39365862 PMC: 11451537. DOI: 10.1126/sciadv.ado5084.

Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling.

Almusallam N, Alonazi A, Bin Dayel A, Almubarak A, Ali R, Althakfi W Saudi Pharm J. 2024; 32(7):102102.

PMID: 39035363 PMC: 11258548. DOI: 10.1016/j.jsps.2024.102102.

Voltage-dependent anion channel 1 (VDAC1) overexpression alleviates cardiac fibroblast activation in cardiac fibrosis via regulating fatty acid metabolism.

Tian G, Zhou J, Quan Y, Kong Q, Li J, Xin Y Redox Biol. 2023; 67:102907.

PMID: 37797372 PMC: 10622884. DOI: 10.1016/j.redox.2023.102907.

References

Gombault A, Baron L, Couillin I . ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol. 2013; 3:414. PMC: 3539150. DOI: 10.3389/fimmu.2012.00414. View

Fusco R, Gugliandolo E, Biundo F, Campolo M, Di Paola R, Cuzzocrea S . Inhibition of inflammasome activation improves lung acute injury induced by carrageenan in a mouse model of pleurisy. FASEB J. 2017; 31(8):3497-3511. DOI: 10.1096/fj.201601349R. View

Musa H, Tellez J, Chandler N, Greener I, Maczewski M, Mackiewicz U . P2 purinergic receptor mRNA in rat and human sinoatrial node and other heart regions. Naunyn Schmiedebergs Arch Pharmacol. 2009; 379(6):541-9. DOI: 10.1007/s00210-009-0403-2. View

Tung H, Lee F, Wang S, Tsai M, Lee J, Huo T . The Beneficial Effects of P2X7 Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis. PLoS One. 2015; 10(5):e0124654. PMC: 4416718. DOI: 10.1371/journal.pone.0124654. View

Birkenfeld A, Jordan J, Dworak M, Merkel T, Burnstock G . Myocardial metabolism in heart failure: Purinergic signalling and other metabolic concepts. Pharmacol Ther. 2018; 194:132-144. DOI: 10.1016/j.pharmthera.2018.08.015. View

Liu J, Li G, Peng H, Tu G, Kong F, Liu S . Sensory-sympathetic coupling in superior cervical ganglia after myocardial ischemic injury facilitates sympathoexcitatory action via P2X7 receptor. Purinergic Signal. 2013; 9(3):463-79. PMC: 3757147. DOI: 10.1007/s11302-013-9367-2. View

Burnstock G, Knight G . Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol. 2004; 240:31-304. DOI: 10.1016/S0074-7696(04)40002-3. View

Abdelaziz H, Shaker M, Hamed M, Gameil N . Repression of acetaminophen-induced hepatotoxicity by a combination of celastrol and brilliant blue G. Toxicol Lett. 2017; 275:6-18. DOI: 10.1016/j.toxlet.2017.04.012. View

Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H . Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011; 123(6):594-604. DOI: 10.1161/CIRCULATIONAHA.110.982777. View

10.

Frangogiannis N . Cardiac fibrosis: Cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med. 2018; 65:70-99. DOI: 10.1016/j.mam.2018.07.001. View

11.

Novitskaya T, Chepurko E, Covarrubias R, Novitskiy S, Ryzhov S, Feoktistov I . Extracellular nucleotide regulation and signaling in cardiac fibrosis. J Mol Cell Cardiol. 2016; 93:47-56. DOI: 10.1016/j.yjmcc.2016.02.010. View

12.

Li J, Wu W, Xin Y, Zhao M, Liu X . Inhibition of Nogo-B promotes cardiac hypertrophy via endoplasmic reticulum stress. Biomed Pharmacother. 2018; 104:193-203. DOI: 10.1016/j.biopha.2018.05.039. View

13.

Mezzaroma E, Toldo S, Farkas D, Seropian I, Van Tassell B, Salloum F . The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci U S A. 2011; 108(49):19725-30. PMC: 3241791. DOI: 10.1073/pnas.1108586108. View

14.

Bageghni S, Hemmings K, Yuldasheva N, Maqbool A, Gamboa-Esteves F, Humphreys N . Fibroblast-specific deletion of interleukin-1 receptor-1 reduces adverse cardiac remodeling following myocardial infarction. JCI Insight. 2019; 5. PMC: 6777910. DOI: 10.1172/jci.insight.125074. View

15.

Xie M, Burchfield J, Hill J . Pathological ventricular remodeling: therapies: part 2 of 2. Circulation. 2013; 128(9):1021-30. PMC: 3829603. DOI: 10.1161/CIRCULATIONAHA.113.001879. View

16.

Sandanger O, Ranheim T, Vinge L, Bliksoen M, Alfsnes K, Finsen A . The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013; 99(1):164-74. DOI: 10.1093/cvr/cvt091. View

17.

Shan L, Jiang T, Ci L, Liu Z, Lv X, Li J . Purine signaling regulating HSCs inflammatory cytokines secretion, activation, and proliferation plays a critical role in alcoholic liver disease. Mol Cell Biochem. 2020; 466(1-2):91-102. DOI: 10.1007/s11010-020-03691-0. View

18.

Banfi C, Ferrario S, De Vincenti O, Ceruti S, Fumagalli M, Mazzola A . P2 receptors in human heart: upregulation of P2X6 in patients undergoing heart transplantation, interaction with TNFalpha and potential role in myocardial cell death. J Mol Cell Cardiol. 2005; 39(6):929-39. DOI: 10.1016/j.yjmcc.2005.09.002. View

19.

Roth G, Johnson C, Abajobir A, Abd-Allah F, Abera S, Abyu G . Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017; 70(1):1-25. PMC: 5491406. DOI: 10.1016/j.jacc.2017.04.052. View

20.

Suetomi T, Willeford A, Brand C, Cho Y, Ross R, Miyamoto S . Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca/Calmodulin-Dependent Protein Kinase II δ Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling. Circulation. 2018; 138(22):2530-2544. PMC: 6309790. DOI: 10.1161/CIRCULATIONAHA.118.034621. View