Proteinase‑activated Receptor 2 Deficiency is a Protective Factor Against Cardiomyocyte Apoptosis During Myocardial Ischemia/reperfusion Injury

Overview

Journal Mol Med Rep

Specialty Molecular Biology

Date 2019 Sep 6

PMID 31485622

Citations 4

Authors

Min Wang

Yiwen Ma

Tiantian Zhang

Lin Gao

Shan Zhang

Qizhi Chen

Affiliations

Soon will be listed here.

Abstract

Previous studies have established that proteinase‑activated receptor 2 (PAR2) activation protects against myocardial ischemia/reperfusion injury (MI/RI). However, the role of PAR2 deficiency in MI/RI remains unclear. The aim of the present study was to examine the effect of PAR2 deficiency on cardiomyocyte apoptosis and to clarify the potential molecular mechanisms for its protective effect against MI/RI. Using a mouse model of MI/RI, cardiac function was evaluated by echocardiography, infarct size was assessed by triphenyltetrazolium chloride staining, and myocardial cell apoptosis was measured by terminal deoxynucleotide transferase‑mediated dUTP nick end‑labeling staining. Annexin V/propidium iodide staining, and expression of Bcl‑2 and cleaved PARP were determined to assess apoptosis in myocardial H9c2 cells exposed to hypoxia/reoxygenation (H/R) injury‑simulating MI/RI. Phosphorylated ERK1/2, JNK, and p38 MAPK protein expression levels were analyzed by western blotting. The findings indicated that PAR2 deficiency markedly reduced cardiomyocyte apoptosis in the MI/RI mouse model, as well as in myocardial H9c2 cells exposed to H/R. Furthermore, PAR2 knockdown clearly prevented phosphorylation of ERK1/2 and JNK in myocardial H9c2 cells. The results revealed that PAR2 deficiency alleviated MI/RI‑associated apoptosis by inhibiting phosphorylation of ERK1/2 and JNK. Therefore, targeted PAR2 silencing may be a potential therapeutic approach for alleviation of MI/RI.

Citing Articles

Xa inhibitor edoxaban ameliorates hepatic ischemia-reperfusion injury via PAR-2-ERK 1/2 pathway.

Maeda K, Kuriyama N, Noguchi D, Ito T, Gyoten K, Hayasaki A PLoS One. 2024; 19(5):e0292628.

PMID: 38748746 PMC: 11095713. DOI: 10.1371/journal.pone.0292628.

Involvement of kallikrein-PAR2-proinflammatory pathway in severe trastuzumab-induced cardiotoxicity.

Sasaki R, Kurebayashi N, Eguchi H, Horimoto Y, Shiga T, Miyazaki S Cancer Sci. 2022; 113(10):3449-3462.

PMID: 35879248 PMC: 9530879. DOI: 10.1111/cas.15508.

YQHX Alleviates H/R-Induced Cardiomyocyte Apoptosis by Downregulating miR-1.

Ge L, Fan Y, Fu L, Guo M, Cao P, Peng C Evid Based Complement Alternat Med. 2021; 2021:4852406.

PMID: 34765002 PMC: 8577916. DOI: 10.1155/2021/4852406.

Mesenchymal stem cells treatment improves vascularization, muscle contraction and VEGF expression, and reduces apoptosis in rat ischemic hind limb.

Chen T, Ye B, Tan J, Yang H, He F, Khalil R Biochem Pharmacol. 2021; 190:114530.

PMID: 33891966 PMC: 8316322. DOI: 10.1016/j.bcp.2021.114530.

References

Schafer C, Williams J . Stress kinases and heat shock proteins in the pancreas: possible roles in normal function and disease. J Gastroenterol. 2000; 35(1):1-9. DOI: 10.1080/003655200750024443. View

Napoli C, Cicala C, Wallace J, De Nigris F, Santagada V, Caliendo G . Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart. Proc Natl Acad Sci U S A. 2000; 97(7):3678-83. PMC: 16299. DOI: 10.1073/pnas.97.7.3678. View

Sabri A, Muske G, Zhang H, Pak E, Darrow A, Andrade-Gordon P . Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res. 2000; 86(10):1054-61. DOI: 10.1161/01.res.86.10.1054. View

Kanke T, Macfarlane S, Seatter M, Davenport E, Paul A, McKenzie R . Proteinase-activated receptor-2-mediated activation of stress-activated protein kinases and inhibitory kappa B kinases in NCTC 2544 keratinocytes. J Biol Chem. 2001; 276(34):31657-66. DOI: 10.1074/jbc.M100377200. View

McLean P, Aston D, Sarkar D, Ahluwalia A . Protease-activated receptor-2 activation causes EDHF-like coronary vasodilation: selective preservation in ischemia/reperfusion injury: involvement of lipoxygenase products, VR1 receptors, and C-fibers. Circ Res. 2002; 90(4):465-72. DOI: 10.1161/hh0402.105372. View

Schmidlin F, Amadesi S, Dabbagh K, Lewis D, Knott P, Bunnett N . Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol. 2002; 169(9):5315-21. DOI: 10.4049/jimmunol.169.9.5315. View

Ferrell W, Lockhart J, Kelso E, Dunning L, Plevin R, Meek S . Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest. 2003; 111(1):35-41. PMC: 151840. DOI: 10.1172/JCI16913. View

Jennings R, Sommers H, SMYTH G, FLACK H, LINN H . Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 1960; 70:68-78. View

Darmoul D, Gratio V, Devaud H, Laburthe M . Protease-activated receptor 2 in colon cancer: trypsin-induced MAPK phosphorylation and cell proliferation are mediated by epidermal growth factor receptor transactivation. J Biol Chem. 2004; 279(20):20927-34. DOI: 10.1074/jbc.M401430200. View

10.

Steinberg S . The cardiovascular actions of protease-activated receptors. Mol Pharmacol. 2004; 67(1):2-11. DOI: 10.1124/mol.104.003103. View

11.

Kim Y, Kim H, Hwa Kwon C, Kim J, Woo J, Jung J . Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells. J Appl Toxicol. 2005; 25(5):374-82. DOI: 10.1002/jat.1081. View

12.

Morris D, Ding Y, Ricks T, Gullapalli A, Wolfe B, Trejo J . Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Res. 2006; 66(1):307-14. DOI: 10.1158/0008-5472.CAN-05-1735. View

13.

Boyd J, Mathur S, Wang Y, Bateman R, Walley K . Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response. Cardiovasc Res. 2006; 72(3):384-93. DOI: 10.1016/j.cardiores.2006.09.011. View

14.

Odashima M, Usui S, Takagi H, Hong C, Liu J, Yokota M . Inhibition of endogenous Mst1 prevents apoptosis and cardiac dysfunction without affecting cardiac hypertrophy after myocardial infarction. Circ Res. 2007; 100(9):1344-52. DOI: 10.1161/01.RES.0000265846.23485.7a. View

15.

Jiang R, Zatta A, Kin H, Wang N, Reeves J, Mykytenko J . PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts. Am J Physiol Heart Circ Physiol. 2007; 293(5):H2845-52. DOI: 10.1152/ajpheart.00209.2007. View

16.

Patel P, Tilley D, Rockman H . Physiologic and cardiac roles of beta-arrestins. J Mol Cell Cardiol. 2008; 46(3):300-8. DOI: 10.1016/j.yjmcc.2008.11.015. View

17.

Bunck A, Engelen M, Schnackenburg B, Furkert J, Bremer C, Heindel W . Feasibility of functional cardiac MR imaging in mice using a clinical 3 Tesla whole body scanner. Invest Radiol. 2009; 44(12):749-56. DOI: 10.1097/RLI.0b013e3181b2c135. View

18.

Tong X, Ding J, Yang J, Liu C, Zhang Y, Li S . [The effect of protease-activated receptor2 on rat apoptotic cardiomyocytes underwent ischemia reperfusion injury]. Zhonghua Xin Xue Guan Bing Za Zhi. 2010; 37(9):832-6. View

19.

Soh U, Dores M, Chen B, Trejo J . Signal transduction by protease-activated receptors. Br J Pharmacol. 2010; 160(2):191-203. PMC: 2874842. DOI: 10.1111/j.1476-5381.2010.00705.x. View

20.

Turer A, Hill J . Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol. 2010; 106(3):360-8. PMC: 2957093. DOI: 10.1016/j.amjcard.2010.03.032. View