Porter Karen E, Turner Neil A, O'Regan David J, Ball Stephen G
Institute for Cardiovascular Research, Academic Unit for Cardiovascular Medicine, Worsley Building, University of Leeds, Leeds LS2 9JT, UK.
Cardiovasc Res. 2004 Dec 1;64(3):507-15. doi: 10.1016/j.cardiores.2004.07.020.
Tumor necrosis factor alpha (TNFalpha) is implicated in myocardial remodeling, a process in which activated cardiac fibroblasts (myofibroblasts) secrete matrix-degrading metalloproteinases (MMPs) and undergo increased proliferation and invasion. Statins are cholesterol-lowering drugs that also have direct cellular effects, which may underlie their ability to reduce myocardial remodeling. This study investigated the effect of TNFalpha on human cardiac myofibroblast proliferation, invasion and MMP-9 secretion, and determined whether these properties were modulated by simvastatin.
Human cardiac myofibroblasts were cultured from right atrial appendage. TNF receptor expression was quantified by immunoblotting. Cell proliferation, invasion, MMP-9 secretion and MMP-9 mRNA expression were determined by cell counting, Matrigel-coated modified Boyden chamber assays, gelatin zymography and RT-PCR, respectively.
Human atrial myofibroblasts expressed the TNF-RI and TNF-RII receptor subtypes. TNFalpha (1 ng/ml) induced a 23.1+/-3.9% increase in cell number after 4 days (P<0.001). Additionally, TNFalpha (1-10 ng/ml) significantly (P<0.01) increased myofibroblast invasion, with a concomitant increase in MMP-9 secretion, that was due to increased MMP-9 mRNA levels. Using TNF-R-specific neutralizing antibodies, we determined that these cellular effects of TNFalpha were predominantly TNF-RI-mediated. Simvastatin (0.1-10 mumol/l) concentration dependently inhibited TNFalpha-induced myofibroblast proliferation, invasion and MMP-9 secretion.
TNFalpha, acting predominantly via the TNF-R1 receptor, increased human atrial myofibroblast proliferation, invasion and MMP-9 secretion, all of which were inhibited by simvastatin. Inhibition of cytokine-induced cardiac myofibroblast activation by statins provides a rationale for their use in patients with cardiac pathologies characterized by adverse myocardial remodeling.
肿瘤坏死因子α（TNFα）与心肌重塑有关，在这一过程中，活化的心脏成纤维细胞（肌成纤维细胞）分泌基质降解金属蛋白酶（MMPs），并经历增殖和侵袭增加。他汀类药物是降低胆固醇的药物，也具有直接的细胞效应，这可能是其减少心肌重塑能力的基础。本研究调查了TNFα对人心脏肌成纤维细胞增殖、侵袭和MMP - 9分泌的影响，并确定这些特性是否受辛伐他汀调节。
从右心耳培养人心脏肌成纤维细胞。通过免疫印迹法定量TNF受体表达。分别通过细胞计数、基质胶包被的改良博伊登室试验、明胶酶谱法和RT - PCR测定细胞增殖、侵袭、MMP - 9分泌和MMP - 9 mRNA表达。
人心房肌成纤维细胞表达TNF - RI和TNF - RII受体亚型。4天后，TNFα（1 ng/ml）使细胞数量增加23.1±3.9%（P<0.001）。此外，TNFα（1 - 10 ng/ml）显著（P<0.01）增加肌成纤维细胞侵袭，并伴随MMP - 9分泌增加，这是由于MMP - 9 mRNA水平升高。使用TNF - R特异性中和抗体，我们确定TNFα的这些细胞效应主要由TNF - RI介导。辛伐他汀（0.1 - 10 μmol/l）浓度依赖性地抑制TNFα诱导的肌成纤维细胞增殖、侵袭和MMP - 9分泌。
TNFα主要通过TNF - R1受体发挥作用，增加人心房肌成纤维细胞增殖、侵袭和MMP - 9分泌，而辛伐他汀可抑制所有这些作用。他汀类药物抑制细胞因子诱导的心脏肌成纤维细胞活化，为其用于以不良心肌重塑为特征的心脏疾病患者提供了理论依据。
