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Article: N-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway

TitleN-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway
Authors
KeywordsHeme oxygenase-1 (HO-1)
Inducible nitric oxide synthase (iNOS)
Macrophage polarization
Myocardial infarction
N-propargyl caffeamide (PACA)
Issue Date2018
PublisherKarger Publishers Open Access. The Journal's web site is located at http://www.karger.com/CPB
Citation
Cellular Physiology and Biochemistry, 2018, v. 47, p. 2544-2557 How to Cite?
AbstractBACKGROUND/AIMS: Macrophages exhibit dynamic pro-inflammatory and resolving activities in myocardial infarction. The present study investigated whether caffeic acid derivatives could induce macrophage polarization towards a resolving M2 phenotype against myocardial infarction injury. METHODS: Western blotting, RT-PCR and flow cytometry techniques are used to evaluate macrophage biomarkers expression and specific proteins in the related signaling pathways. Ligation of the left anterior descending artery induced rat model of myocardial infarction, TTC staining and immunohistochemical staining are used to examine cardioprotective effect in vivo. RESULTS: We initially evaluated the anti-inflammatory activity of four caffeic acid derivatives including n-propargyl caffeamide (PACA) in RAW264.7 macrophages. As result, PACA selectively suppressed the up-regulation of inducible nitric oxide synthase (iNOS) over cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated cells. We subsequently examined the effects of PACA on macrophage polarization by determining macrophage biomarkers. PACA down-regulated M1 biomarkers (e.g., iNOS, tumor necrosis factor-α (TNF-α), C-X-C motif chemokine 10 (CXCL10) and CD80) but up-regulated M2 biomarkers (e.g., Ym-1 and arginase-1). On the other hand, PACA suppressed macrophage chemotaxis while enhanced macrophage phagocytosis. We further examined the in vivo cardioprotective activity of PACA in a rat model of myocardial infarction. Following ligation of the left anterior descending artery, PACA treatment effectively reduced myocardial infarct size and promoted macrophage M2 polarization. We finally explored the underlying mechanisms. We found that PACA attenuated LPS-induced NF-ĸB activation while activated Nrf2/HO-1 pathway. HO-1 inhibitor SnPP attenuated the effects of PACA on iNOS expression in LPS-challenged macrophages, possibly by regulating the cross-talk between HO-1 and NF-ĸB pathways. CONCLUSIONS: The key finding from the present study was that PACA promoted timely switch of macrophage phenotypes from pro-inflammatory M1 to resolving M2. We anticipate that PACA is a potential drug candidate for the resolution of inflammation and cardiac repair after myocardial infarction.
Persistent Identifierhttp://hdl.handle.net/10722/272135
ISSN
2017 Impact Factor: 5.5
2015 SCImago Journal Rankings: 1.139

 

DC FieldValueLanguage
dc.contributor.authorCHENG, Y-
dc.contributor.authorYANG, C-
dc.contributor.authorLUO, D-
dc.contributor.authorLi, X-
dc.contributor.authorLe, XC-
dc.contributor.authorRong, J-
dc.date.accessioned2019-07-20T10:36:21Z-
dc.date.available2019-07-20T10:36:21Z-
dc.date.issued2018-
dc.identifier.citationCellular Physiology and Biochemistry, 2018, v. 47, p. 2544-2557-
dc.identifier.issn1015-8987-
dc.identifier.urihttp://hdl.handle.net/10722/272135-
dc.description.abstractBACKGROUND/AIMS: Macrophages exhibit dynamic pro-inflammatory and resolving activities in myocardial infarction. The present study investigated whether caffeic acid derivatives could induce macrophage polarization towards a resolving M2 phenotype against myocardial infarction injury. METHODS: Western blotting, RT-PCR and flow cytometry techniques are used to evaluate macrophage biomarkers expression and specific proteins in the related signaling pathways. Ligation of the left anterior descending artery induced rat model of myocardial infarction, TTC staining and immunohistochemical staining are used to examine cardioprotective effect in vivo. RESULTS: We initially evaluated the anti-inflammatory activity of four caffeic acid derivatives including n-propargyl caffeamide (PACA) in RAW264.7 macrophages. As result, PACA selectively suppressed the up-regulation of inducible nitric oxide synthase (iNOS) over cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated cells. We subsequently examined the effects of PACA on macrophage polarization by determining macrophage biomarkers. PACA down-regulated M1 biomarkers (e.g., iNOS, tumor necrosis factor-α (TNF-α), C-X-C motif chemokine 10 (CXCL10) and CD80) but up-regulated M2 biomarkers (e.g., Ym-1 and arginase-1). On the other hand, PACA suppressed macrophage chemotaxis while enhanced macrophage phagocytosis. We further examined the in vivo cardioprotective activity of PACA in a rat model of myocardial infarction. Following ligation of the left anterior descending artery, PACA treatment effectively reduced myocardial infarct size and promoted macrophage M2 polarization. We finally explored the underlying mechanisms. We found that PACA attenuated LPS-induced NF-ĸB activation while activated Nrf2/HO-1 pathway. HO-1 inhibitor SnPP attenuated the effects of PACA on iNOS expression in LPS-challenged macrophages, possibly by regulating the cross-talk between HO-1 and NF-ĸB pathways. CONCLUSIONS: The key finding from the present study was that PACA promoted timely switch of macrophage phenotypes from pro-inflammatory M1 to resolving M2. We anticipate that PACA is a potential drug candidate for the resolution of inflammation and cardiac repair after myocardial infarction.-
dc.languageeng-
dc.publisherKarger Publishers Open Access. The Journal's web site is located at http://www.karger.com/CPB-
dc.relation.ispartofCellular Physiology and Biochemistry-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectHeme oxygenase-1 (HO-1)-
dc.subjectInducible nitric oxide synthase (iNOS)-
dc.subjectMacrophage polarization-
dc.subjectMyocardial infarction-
dc.subjectN-propargyl caffeamide (PACA)-
dc.titleN-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway-
dc.typeArticle-
dc.identifier.emailLi, X: xuechenl@hku.hk-
dc.identifier.emailRong, J: jrong@hku.hk-
dc.identifier.authorityLi, X=rp00742-
dc.identifier.authorityRong, J=rp00515-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1159/000491651-
dc.identifier.pmid29996121-
dc.identifier.scopuseid_2-s2.0-85049872325-
dc.identifier.hkuros298808-
dc.identifier.volume47-
dc.identifier.spage2544-
dc.identifier.epage2557-
dc.publisher.placeSwitzerland-

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