Abstract
Ethnopharmacological relevance: Curcumin is a bright yellow chemical produced by plants of the Curcuma longa species. Chemically, curcumin is a diarylheptanoid, belonging to the group of curcuminoids. The therapeutic potential of curcumin has been widely investigated, including its utilization in various of cardiovascular diseases. However, its effect in cardiac remodeling post myocardial infarction and underlying mechanism remains to be uncover. Aim: To evaluate the therapeutic effect and underlying mechanism of curcumin on cardiac fibrosis after myocardial infarction via macrophage-fibroblast crosstalk. Methods: Male C57BL/6 (C57) mice were subjected to left anterior descending coronary artery ligation to establish myocardial infarction and intragastrically fed vehicle or curcumin (50 mg/kg or 100 mg/kg) for 4 weeks. In parallel, neonatal rat cardiac fibroblasts were isolated and co-cultured with liposaccharide (LPS− or LPS+) curcumin-treated macrophages, followed by TGF-β stimulation for 24 h. Cardiac function was determined by 2-dimensional echocardiography, and cardiac fibrosis was measured by picrosirius red staining. Apoptosis of macrophages was investigated by flow cytometry; all pro-fibrotic protein expression (EDA-Fibronectin, Periostin, Vimentin, and α-SMA) as well as TGF-βR1 downstream signaling activation reflected by phosphorylated SMAD2/3 (p-SMAD2 and p-SMAD3) were demonstrated by western blotting. Results: Curcumin significantly ameliorated the inflammation process subsequent to myocardial infarction, reflected by decreased expression of CD68+ and CD3+ cells, accompanied by dramatically improved cardiac function compared with the placebo group. In addition, cardiac fibrosis is inhibited by curcumin administration. Interestingly, no significant reduction in fibrotic gene expression was observed when isolated cardiac fibroblasts were directly treated with curcumin in vitro; however, pro-fibrotic protein expression was significantly attenuated in CF, which was co-cultured with LPS-stimulated macrophages under curcumin treatment compared with the placebo group. Mechanistically, we discovered that curcumin significantly downregulated pro-inflammatory cytokines in macrophages, which in turn inhibited IL18 expression in co-cultured cardiac fibroblasts using bulk RNA sequencing, and the TGF-β1-p-SMAD2/3 signaling network was also discovered as the eventual target downstream of IL18 in curcumin-mediated anti-fibrosis signaling. Conclusion: Curcumin improves cardiac function and reduces cardiac fibrosis after myocardial infarction. This effect is mediated by the inhibition of macrophage-fibroblast crosstalk in the acute phase post-MI and retrained activation of IL18-TGFβ1-p-SMAD2/3 signaling in cardiac fibroblasts.
Highlights
Cardiovascular diseases, especially ischemic heart disease, remain the leading cause of death worldwide
At 7 days post-myocardial infarction (MI) surgery, we discovered significantly inhibited inflammation activation reflected by reduced CD68+ and CD3+ cells detected in the peri-infarcted area in the curcumin group compared with the placebo group, while no difference in CD68+ and CD3+ cell counts was observed between the high-dose curcumin group (100 mg/kg) and the low-dose curcumin group (50 mg/kg) (Figures 1A–D)
Cardiac function in the MI + curcumin group exhibited significant improvement compared with the placebo group 1 month after MI, with no obvious change observed 7 days post-MI between the two groups, as demonstrated by ejection fraction (EF%) and fraction shortening (FS%) (Figures 1E–G), in addition, the chamber of left ventricle in systolic phase was dramatically decreased in MI + curcumin group compared with MI group (LVID s), while no significant change were detected between groups in diastolic phase (LVID d) (Figures 1H,I)
Summary
Cardiovascular diseases, especially ischemic heart disease, remain the leading cause of death worldwide. Monocytes and macrophages play a critical role in regulating fibrotic responses in various tissues, including cardiac tissue after ischemic stimulation (Wynn and Vannella, 2016). The normal adult mammalian myocardium contains a relatively small population of resident macrophages (Epelman et al, 2014), (Heidt et al, 2014) which have been suggested to play a role in cardiac homeostasis by facilitating atrioventricular conduction (Hulsmans et al, 2017). Macrophages in injured hearts are highly heterogeneous and exhibit functional and phenotypic versatility that enables them to participate in a wide range of processes, including inflammation regulation, fibrosis, matrix remodeling, angiogenesis, and regeneration (Honold and Nahrendorf, 2018). Subsets of activated macrophages may regulate fibrosis by serving as a major source of cytokines and growth factors with fibrogenic properties, secretion of proteases that participate in matrix remodeling, and production of matricellular proteins. Proinflammatory cytokines (such as IL-1β, IL-6, and TNF-α) secreted in many cardiac fibrotic conditions may promote a fibrogenic macrophage phenotype by inducing transcription of members of the TGF-β superfamily
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