Curcumin Reduces Cardiac Fibrosis by Inhibiting Myofibroblast Differentiation and Decreasing Transforming Growth Factor β1 and Matrix Metalloproteinase 9/Tissue Inhibitor of Metalloproteinase 1

Objective： To study the effect of curcumin on fibroblasts in rats with cardiac fibrosis. Methods： The rats were randomly divided into 4 groups（n=12 in each group）： the normal control, isoproterenol（ISO）, ISO combined with low-dose curcumin（ISO＋Cur-L）, and ISO combined with high-dose curcumin（ISO＋Cur-H） groups. ISO＋Cur-L and ISO＋Cur-H groups were treated with curcumin（150 or 300 mg·kg-1·day-1） for 28 days. The primary culture of rat cardiac fibroblast was processed by trypsin digestion method in vitro. The 3rd to 5th generation were used for experiment. Western blot method was used to test the expression of collagen type Ⅰ/Ⅲ, α-smooth muscle actin（α-SMA）, transforming growth factor（TGF）-β1, matrix metalloproteinase（MMP）-9 and tissue inhibitor of metalloproteinase（TIMP）-1. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetr-azolium bromide（MTT） assay was applied to test the proliferation of fibroblast. Result： Curcumin significantly decreased interstitial and perivascular myocardial collagen deposition and cardiac weight index with reducing protein expression of collagen type Ⅰ/Ⅲ in hearts（P〈0.05）. In addition, curcumin directly inhibited angiotensin（Ang） Ⅱ-induced fibroblast proliferation and collagen type Ⅰ/Ⅲ expression in cardiac fibroblasts（P〈0.05）. Curcumin also inhibited fibrosis by inhibiting myofibroblast differentiation, decreased TGF-β1, MMP-9 and TIMP-1 expression（P〈0.05） but had no effects on Smad3 in Ang Ⅱ incubated cardiac fibroblasts. Conclusions： Curcumin reduces cardiac fibrosis in rats and Ang Ⅱ-induced fibroblast proliferation by inhibiting myofibroblast differentiation, decreasing collagen synthesis and accelerating collagen degradation through reduction of TGF-β1, MMPs/TIMPs. The present findings also provided novel insights into the role of curcumin as an anti-fibrotic agent for the treatment of cardiac fibrosis.

Cytokine receptor-like factor 1(CRLF1)promotes cardiac fibrosis via ERK1/2 signaling pathway

Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease.Anti-fibrosis treatment is a significant therapy for heart disease,but there is still no thorough understanding of fibrotic mechanisms.This study was carried out to ascertain the functions of cytokine receptor-like factor 1(CRLF1)in cardiac fibrosis and clarify its regulatory mechanisms.We found that CRLF1 was expressed predominantly in cardiac fibroblasts.Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction,but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-β1(TGF-β1).Gain-and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts(NMCFs)with or without TGF-β1 stimulation.CRLF1 overexpression increased cell viability,collagen production,cell proliferation capacity,and myofibroblast transformation of NMCFs with or without TGF-β1 stimulation,while silencing of CRLF1 had the opposite effects.An inhibitor of the extracellular signal-regulated kinase 1/2(ERK1/2)signaling pathway and different inhibitors of TGF-β1 signaling cascades,comprising mothers against decapentaplegic homolog(SMAD)-dependent and SMAD-independent pathways,were applied to investigate the mechanisms involved.CRLF1 exerted its functions by activating the ERK1/2 signaling pathway.Furthermore,the SMAD-dependent pathway,not the SMAD-independent pathway,was responsible for CRLF1 up-regulation in NMCFs treated with TGF-β1.In summary,activation of the TGF-β1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression.CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway.CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.