Abstract
The timely regulation of inflammatory M1 macrophage polarization toward regenerative M2 macrophages suggests the possibility of immunotherapy after myocardial infarction (MI). C1q/TNF‐related protein‐9 (CTRP9) has anti‐inflammatory effects and can ameliorate heart function in mice after long‐term myocardial infarction. The role of CTRP9 in macrophage polarization remains completely unclear. This study determined whether CTRP9 can preserve post‐MI early cardiac function through the regulation of macrophage polarization. In the present study, an adenovirus‐delivered CTRP9 supplement promoted macrophage polarization at Day 3 post MI and improved cardiac function at Day 7 post MI. Pretreatment with gCTRP9 promoted the M1 to M2 polarization transition and attenuated inflammation after lipopolysaccharide + interferon‐γ stimulation; the effects were partly abrogated by the adenosine monophosphate kinase (AMPK) inhibitor compound C and were obviously reinforced by pyrrolidine dithiocarbamate, a nuclear factor‐κB (NF‐κB) inhibitor. Meanwhile, CTPR9 markedly reduced the expression of toll‐like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and NF‐κB p65 phosphorylation by promoting AMPK phosphorylation in vivo and in vitro. Moreover, the competitive binding of gCTRP9 and LPS to the myeloid differentiation protein 2 (MD2)/TLR4 complex was associated with direct binding to MD2, thereby inhibiting the downstream signaling molecule MyD88. Taken together, we demonstrated that CTRP9 improved post‐MI early cardiac function, at least in part, by modulating M1/M2 macrophage polarization, largely via the TLR4/MD2/MyD88 and AMPK‐NF‐κB pathways.
Highlights
Inflammation subsidence is important for improving tissue injury and cardiac function after myocardial infarction (MI) and requires the concerted action of macrophages
We found that overexpression of C1q/TNF‐related protein‐9 (CTRP9) in an MI model can enhance M2 macrophage polarization and improve cardiac function in the early stage post MI. globular domain isoform of CTRP9 (gCTRP9) can reduce the inflammatory response by promoting the M1 to M2 macrophage transition in vitro, which was mechanistically associated with the toll‐like receptor 4 (TLR4)/myeloid differentiation protein 2 (MD2)/myeloid differentiation factor 88 (MyD88) and adenosine monophosphate kinase (AMPK)‐nuclear factor‐κB (NF‐κB) signaling pathways
The results showed that the effect of gCTRP9 comprehensively began at a concentration of 3 μg/ml, and the expression of M2 instead of M1 marker was improved at 1 μg/ml, which differed from the 1 μg/ml inhibitory concentration of CTRP9 in the oxidized low‐density lipoprotein‐induced inflammatory reaction (Zhang et al, 2016); we adopted the concentration of 3 μg/ml in the following experiments. gCTRP9 had a similar effect on macrophage polarization in the absence of LPS IFN‐γ intervention (Figure 3a‐i)
Summary
Inflammation subsidence is important for improving tissue injury and cardiac function after myocardial infarction (MI) and requires the concerted action of macrophages. Positively transforming to the M2 phenotype at 3 days is a therapeutic key to reduce adverse LV remodeling after MI It has been well‐known that macrophages are functionally polarized into M1 and M2 cells in response to infection with microorganisms and host mediators. We have known that the signaling molecules TLR4, AMPK, NF‐κB, and PPAR‐γ, which are associated with CTRP9, are involved in macrophage polarization. Given this evidence, whether CTRP9 can regulate cardiac function in the early stage post MI by affecting macrophage polarization and the specific mechanism remain largely unknown. We provided evidence that CTRP9 acts as a critical regulator of cardiac function and macrophage polarization through suppression of the NF‐κB signaling pathway
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