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Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels.
Exp Ther Med. 2019 Nov; 18(5):3636-3642.ET

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.

Authors+Show Affiliations

Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA. Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA. Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31602241

Citation

Zhong, Beihua, et al. "Protease-activated Receptor 2 Protects Against Myocardial Ischemia-reperfusion Injury Through the Lipoxygenase Pathway and TRPV1 Channels." Experimental and Therapeutic Medicine, vol. 18, no. 5, 2019, pp. 3636-3642.
Zhong B, Ma S, Wang DH. Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels. Exp Ther Med. 2019;18(5):3636-3642.
Zhong, B., Ma, S., & Wang, D. H. (2019). Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels. Experimental and Therapeutic Medicine, 18(5), 3636-3642. https://doi.org/10.3892/etm.2019.7987
Zhong B, Ma S, Wang DH. Protease-activated Receptor 2 Protects Against Myocardial Ischemia-reperfusion Injury Through the Lipoxygenase Pathway and TRPV1 Channels. Exp Ther Med. 2019;18(5):3636-3642. PubMed PMID: 31602241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels. AU - Zhong,Beihua, AU - Ma,Shuangtao, AU - Wang,Donna H, Y1 - 2019/09/09/ PY - 2018/07/23/received PY - 2019/07/22/accepted PY - 2019/10/12/entrez PY - 2019/10/12/pubmed PY - 2019/10/12/medline KW - calcitonin gene-related peptide KW - protease-activated receptors KW - reperfusion injury KW - substance P KW - vanilloid receptor SP - 3636 EP - 3642 JF - Experimental and therapeutic medicine JO - Exp Ther Med VL - 18 IS - 5 N2 - 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. SN - 1792-0981 UR - https://www.unboundmedicine.com/medline/citation/31602241/Protease_activated_receptor_2_protects_against_myocardial_ischemia_reperfusion_injury_through_the_lipoxygenase_pathway_and_TRPV1_channels_ L2 - https://www.ingentaconnect.com/openurl?genre=article&amp;issn=1792-0981&amp;volume=18&amp;issue=5&amp;spage=3636&amp;aulast=Zhong DB - PRIME DP - Unbound Medicine ER -
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