TY - JOUR
T1 - N-Propargyl caffeamide skews macrophages towards a resolving M2-Like phenotype against myocardial ischemic injury via activating Nrf2/HO-1 pathway and inhibiting NF-KB Pathway
AU - Cheng, Yuanyuan
AU - Yang, Chuanbin
AU - Luo, Dan
AU - Li, Xuechen
AU - Le, X. Chris
AU - Rong, Jianhui
N1 - Funding Information:
This work was supported by GRF grants ( 猃礃猃球爃笃猃省 猃? 猃瘃砃球猃砂I from the Research Grants Counci? of Hong Kong Government (to J.R.) and two interna? Seed Funds for Basic Research Programme from University of Hong Kong ( 球爃猃瘃猃猃猃眃笃猃甃爁 球爃猃眃猃猃猃眃笃球瘃眂I. Y.Y. Cheng, C.B. Yang and D. Luo performed experiments, ana?yzed data, and wrote the manuscript. X.C. Li and X.C. Le provided the technica? support and discussed the resu?ts. J. Rong designed the research, supervised data ana? ysis and wrote the artic?e.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Background/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-KB 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-KB 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.
AB - Background/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-KB 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-KB 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.
KW - Heme oxygenase-1 (HO-1)
KW - Inducible nitric oxide synthase (iNOS)
KW - Macrophage polarization
KW - Myocardial infarction
KW - N-propargyl caffeamide (PACA)
UR - http://www.scopus.com/inward/record.url?scp=85049872325&partnerID=8YFLogxK
U2 - 10.1159/000491651
DO - 10.1159/000491651
M3 - Journal article
C2 - 29996121
AN - SCOPUS:85049872325
SN - 1015-8987
VL - 47
SP - 2544
EP - 2557
JO - Cellular Physiology and Biochemistry
JF - Cellular Physiology and Biochemistry
IS - 6
ER -
