Protease‑activated receptor 2 protects against myocardial ischemia‑reperfusion injury through the lipoxygenase pathway and TRPV1 channels

Zhong,Beihua; Ma,Shuangtao; Wang,Donna  H.

doi:10.3892/etm.2019.7987

Protease‑activated receptor 2 protects against myocardial ischemia‑reperfusion injury through the lipoxygenase pathway and TRPV1 channels

Authors:
- Beihua Zhong
- Shuangtao Ma
- Donna H. Wang
View Affiliations

Affiliations: Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
Published online on: September 9, 2019 https://doi.org/10.3892/etm.2019.7987
Pages: 3636-3642

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

This study tests the hypothesis that the lipoxygenase (LOX) pathway mediates protease‑activated receptor (PAR) 2‑induced activation of the transient receptor potential vanilloid receptor 1 (TRPV1) to protect the heart from ischemia/reperfusion (I/R) injury. SLIGRL, a PAR2 activating peptide, was administered prior to reperfusion following left anterior descending coronary artery ligation in wild type (WT) and TRPV1 knockout (TRPV1‑/‑) mice. In a Langendorffly perfused heart I/R model, hemodynamic parameters, including left ventricular end‑diastolic pressure, left ventricular developed pressure, coronary blood flow and left ventricular peak +dP/dt were evaluated after I/R. SLIGRL reduced the cardiac infarct size in WT and TRPV1‑/‑ mice with a greater effect in the former strain (P<0.05). SLIGRL increased plasma levels of calcitonin gene‑related peptide (CGRP) and substance P in WT (both P<0.05) but not in TRPV1‑/‑ mice. Pretreatment with CGRP8‑37 (a CGRP receptor antagonist) or RP67580 (a neurokinin‑1 receptor antagonist) alone had no effect on SLIGRL‑induced cardiac protection in either strain. However, combined administration of CGRP8‑37 and RP67580 abolished SLIGRL‑induced cardiac protection in WT but not in TRPV1‑/‑ mice. Nordihydroguaiaretic acid (a general LOX inhibitor) and baicalein (a 12‑LOX inhibitor), but not indomethacin (a cyclooxygenase inhibitor) and hexanamide (a selective cytochrome P450 epoxygenase inhibitor), abolished the protective effects of SLIGRL in WT (all P<0.05) but not in TRPV1‑/‑ hearts. These data suggested that PAR2, possibly via 12‑LOX, activates TRPV1 and leads to CGRP and substance P release to prevent I/R injury in the heart, indicating that the 12‑LOX‑TRPV1 pathway conveys cardiac protection to alleviate myocardial infarction.

View Figures

View References

1	Ossovskaya VS and Bunnett NW: Protease-activated receptors: Contribution to physiology and disease. Physiol Rev. 84:579–621. 2004. View Article : Google Scholar : PubMed/NCBI
2	Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N, Luger TA and Hollenberg MD: Proteinase-activated receptors: Transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev. 26:1–43. 2005. View Article : Google Scholar : PubMed/NCBI
3	Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, et al: Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 6:151–158. 2000. View Article : Google Scholar : PubMed/NCBI
4	Gunthorpe MJ, Benham CD, Randall A and Davis JB: The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci. 23:183–191. 2002. View Article : Google Scholar : PubMed/NCBI
5	Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI and Julius D: Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 288:306–313. 2000. View Article : Google Scholar : PubMed/NCBI
6	Dai Y, Moriyama T, Higashi T, Togashi K, Kobayashi K, Yamanaka H, Tominaga M and Noguchi K: Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J Neurosci. 24:4293–4299. 2004. View Article : Google Scholar : PubMed/NCBI
7	McLean PG, Aston D, Sarkar D and 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. 90:465–472. 2002. View Article : Google Scholar : PubMed/NCBI
8	Zhong B and Wang DH: TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol. 293:H1791–H1798. 2007. View Article : Google Scholar : PubMed/NCBI
9	Napoli C, Cicala C, Wallace JL, de Nigris F, Santagada V, Caliendo G, Franconi F, Ignarro LJ and Cirino G: Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart. Proc Natl Acad Sci USA. 97:3678–3683. 2000. View Article : Google Scholar : PubMed/NCBI
10	Robin J, Kharbanda R, McLean P, Campbell R and Vallance P: Protease-activated receptor 2-mediated vasodilatation in humans in vivo: Role of nitric oxide and prostanoids. Circulation. 107:954–959. 2003. View Article : Google Scholar : PubMed/NCBI
11	Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D and Oh U: Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. Proc Natl Acad Sci USA. 97:6155–6160. 2000. View Article : Google Scholar : PubMed/NCBI
12	Starkopf J, Andreasen TV, Bugge E and Ytrehus K: Lipid peroxidation, arachidonic acid and products of the lipoxygenase pathway in ischaemic preconditioning of rat heart. Cardiovasc Res. 37:66–75. 1998. View Article : Google Scholar : PubMed/NCBI
13	Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, Ith B, Melo LG, Zhang L, Ingwall JS, et al: Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res. 89:168–173. 2001. View Article : Google Scholar : PubMed/NCBI
14	Cattaruzza F, Cenac N, Barocelli E, Impicciatore M, Hyun E, Vergnolle N and Sternini C: Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents. Am J Pathol. 169:177–188. 2006. View Article : Google Scholar : PubMed/NCBI
15	Zhong B and Wang DH: N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1. Am J Physiol Heart Circ Physiol. 295:H728–H735. 2008. View Article : Google Scholar : PubMed/NCBI
16	Hochhauser E, Alterman I, Weinbroum A, Barak Y, Harell D, Raz A, Erman A and Vidne B: Effects of vasoactive substances released from ischemic reperfused liver on the isolated rat heart. Exp Clin Cardiol. 6:29–34. 2001.PubMed/NCBI
17	Nayeem MA, Ponnoth DS, Boegehold MA, Zeldin DC, Falck JR and Mustafa SJ: High-salt diet enhances mouse aortic relaxation through adenosine A2A receptor via CYP epoxygenases. Am J Physiol Regul Integr Comp Physiol. 296:R567–R574. 2009. View Article : Google Scholar : PubMed/NCBI
18	Zhong B and Wang DH: Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: Role of transient receptor potential vanilloid receptors. Am J Physiol Regul Integr Comp Physiol. 297:R1681–R1690. 2009. View Article : Google Scholar : PubMed/NCBI
19	Amadesi S, Cottrell GS, Divino L, Chapman K, Grady EF, Bautista F, Karanjia R, Barajas-Lopez C, Vanner S, Vergnolle N and Bunnett NW: Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J Physiol. 575:555–571. 2006. View Article : Google Scholar : PubMed/NCBI
20	Starr A, Graepel R, Keeble J, Schmidhuber S, Clark N, Grant A, Shah AM and Brain SD: A reactive oxygen species-mediated component in neurogenic vasodilatation. Cardiovasc Res. 78:139–147. 2008. View Article : Google Scholar : PubMed/NCBI
21	Wang DH: The vanilloid receptor and hypertension. Acta Pharmacol Sin. 26:286–294. 2005. View Article : Google Scholar : PubMed/NCBI
22	Wang L and Wang DH: TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation. 112:3617–3623. 2005. View Article : Google Scholar : PubMed/NCBI
23	Athanasiou A, Smith PA, Vakilpour S, Kumaran NM, Turner AE, Bagiokou D, Layfield R, Ray DE, Westwell AD, Alexander SP, et al: Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: How vanilloids cause non-vanilloid receptor mediated cell death. Biochem Biophys Res Commun. 354:50–55. 2007. View Article : Google Scholar : PubMed/NCBI
24	Nilius B, Owsianik G, Voets T and Peters JA: Transient receptor potential cation channels in disease. Physiol Rev. 87:165–217. 2007. View Article : Google Scholar : PubMed/NCBI
25	Wang Y, Babánková D, Huang J, Swain GM and Wang DH: Deletion of transient receptor potential vanilloid type 1 receptors exaggerates renal damage in deoxycorticosterone acetate-salt hypertension. Hypertension. 52:264–270. 2008. View Article : Google Scholar : PubMed/NCBI
26	Helyes Z, Elekes K, Németh J, Pozsgai G, Sándor K, Kereskai L, Börzsei R, Pintér E, Szabó A and Szolcsányi J: Role of transient receptor potential vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse. Am J Physiol Lung Cell Mol Physiol. 292:L1173–L1181. 2007. View Article : Google Scholar : PubMed/NCBI
27	Brain SD, Williams TJ, Tippins JR, Morris HR and MacIntyre I: Calcitonin gene-related peptide is a potent vasodilator. Nature. 313:54–56. 1985. View Article : Google Scholar : PubMed/NCBI
28	Asimakis GK, DiPette DJ, Conti VR, Holland OB and Zwischenberger JB: Hemodynamic action of calcitonin gene-related peptide in the isolated rat heart. Life Sci. 41:597–603. 1987. View Article : Google Scholar : PubMed/NCBI
29	Li W, Wang T, Ma C, Xiong T, Zhu Y and Wang X: Calcitonin gene-related peptide inhibits interleukin-1beta-induced endogenous monocyte chemoattractant protein-1 secretion in type II alveolar epithelial cells. Am J Physiol Cell Physiol. 291:C456–C465. 2006. View Article : Google Scholar : PubMed/NCBI
30	Harzenetter MD, Novotny AR, Gais P, Molina CA, Altmayr F and Holzmann B: Negative regulation of TLR responses by the neuropeptide CGRP is mediated by the transcriptional repressor ICER. J Immunol. 179:607–615. 2007. View Article : Google Scholar : PubMed/NCBI
31	O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP and Shanahan F: The role of substance P in inflammatory disease. J Cell Physiol. 201:167–180. 2004. View Article : Google Scholar : PubMed/NCBI
32	Kramer JH, Phillips TM and Weglicki WB: Magnesium-deficiency-enhanced post-ischemic myocardial injury is reduced by substance P receptor blockade. J Mol Cell Cardiol. 29:97–110. 1997. View Article : Google Scholar : PubMed/NCBI
33	Souza DG, Mendonça VA, de A Castro MS, Poole S and Teixeira MM: Role of tachykinin NK receptors on the local and remote injuries following ischaemia and reperfusion of the superior mesenteric artery in the rat. Br J Pharmacol. 135:303–312. 2002. View Article : Google Scholar : PubMed/NCBI
34	Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, et al: Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol. 578:715–733. 2007. View Article : Google Scholar : PubMed/NCBI
35	Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S and Tominaga M: Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain. 1:32005. View Article : Google Scholar : PubMed/NCBI
36	Shinmura K, Tamaki K, Sato T, Ishida H and Bolli R: Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor. Am J Physiol Heart Circ Physiol. 288:H2093–H2101. 2005. View Article : Google Scholar : PubMed/NCBI
37	Camitta MG, Gabel SA, Chulada P, Bradbury JA, Langenbach R, Zeldin DC and Murphy E: Cyclooxygenase-1 and −2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning. Circulation. 104:2453–2458. 2001. View Article : Google Scholar : PubMed/NCBI
38	Sexton A, McDonald M, Cayla C, Thiemermann C and Ahluwalia A: 12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1. FASEB J. 21:2695–2703. 2007. View Article : Google Scholar : PubMed/NCBI
39	Gross GJ, Falck JR, Gross ER, Isbell M, Moore J and Nithipatikom K: Cytochrome P450 and arachidonic acid metabolites: Role in myocardial ischemia/reperfusion injury revisited. Cardiovasc Res. 68:18–25. 2005. View Article : Google Scholar : PubMed/NCBI
40	Ding Z, Gödecke A and Schrader J: Contribution of cytochrome P450 metabolites to bradykinin-induced vasodilation in endothelial NO synthase deficient mouse hearts. Br J Pharmacol. 135:631–638. 2002. View Article : Google Scholar : PubMed/NCBI