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

Abstract

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-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.

Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils

“…Caffeic acid has been considered as the active phytochemical in plant extracts, caffeic acid derivatives and was used in development of novel hybrid molecules that inhibit the expression of COX-2 (Kulabas et al, 2018). The biological effect of caffeic acid might be related to suppression of COX-2 protein at mRNA levels (Lee et al, 2018;Michaluart et al, 1999), inhibition of NF-kB pathway (Cheng et al, 2018) or activation of HO-1 pathway (Choi et al, 2018).…”

Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases

“…Caffeic acid phenethyl ester derivative compounds promote the switch of macrophage phenotypes from proinflammatory M1 to resolving M2. Besides, the effect is dependent on the activation of the Nrf2/HO-1 pathway (184). Moreover, CAPE induces HO-1 in microglia cells, reducing NO production (185).…”

Therapeutic efficacy of Schistosoma japonicum cystatin on sepsis-induced cardiomyopathy in a mouse model

“…The primers (GAPDH, TNF-α and IL-6) were designed and synthesized by Sangon Biotech (Shanghai, China). The forward and reverse primers of target genes are listed in Additional file 1: Table S1 [29][30][31].…”