Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity
Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity
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DOI：
10.1097/hjh.0000000000000149
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发表时间：
2014-05-01
影响因子：
4.9
通讯作者：
Cachofeiro, Victoria
中科院分区：
文献类型：
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作者：
Martinez-Martinez, Ernesto;Jurado-Lopez, Raquel;Cachofeiro, Victoria
目的：瘦素是一种促心脏纤维化因子。然而，这种影响的机制尚不清楚。因此，我们试图阐明参与这一过程的介质和瘦素在与obesity.Methods相关的心脏纤维化中的潜在作用：雄性Wistar大鼠喂养高脂饮食（HFD; 33.5%脂肪），或标准饮食（3.5%脂肪）6 weeks.Results：HFD动物显示心肌肥大，纤维化和增加O-2（-）生产的评估由二氢乙锭。两组心脏结构和收缩功能的超声心动图参数相似。心脏瘦素，胶原蛋白I，半乳糖凝集素-3和转化生长因子β（TGF-β）的水平在HFD高于对照组。在心肌成纤维细胞中，瘦素（10-100 ng/ml）增加O-2（-）、胶原I、半乳糖凝集素-3、TGF-β和结缔组织生长因子（CTGF）的产生。这些作用被褪黑素（10（-3）mmol/l）或mTOR抑制剂雷帕霉素（10（-4）mmol/l）的存在所阻止。用N-乙酰乳糖胺（LacNac 10（-3）mmol/l）阻断半乳糖凝集素-3的活性可减少I型胶原和O-2（.-）leptin诱导的产生。褪黑激素不改变瘦素诱导的mTOR下游介质p70 S6激酶的活化/磷酸化。瘦素降低了金属蛋白酶（MMP）2的活性，褪黑素、雷帕霉素或LacNac的存在无法阻止它。结论：数据表明，心脏局部产生的瘦素可能通过影响胶原周转参与HFD中观察到的纤维化。瘦素诱导的胶原蛋白合成似乎是由半乳糖凝集素-3、TGF-β和CTGF的产生介导的，所述半乳糖凝集素-3、TGF-β和CTGF的产生是通过mTOR途径的激活而增加的氧化应激来进行的。
Objective:Leptin acts as a cardiac profibrotic factor. However, the mechanisms underlying this effect are unclear. Therefore, we sought to elucidate the mediators involved in this process and the potential role of leptin in cardiac fibrosis associated with obesity.Methods:Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks.Results:HFD animals show cardiac hypertrophy, fibrosis and an increase in O-2(-) production as evaluated by dihydroethidium. Echocardiographic parameters of cardiac structure and systolic function were similar in both groups. Cardiac levels of leptin, collagen I, galectin-3 and transforming growth factor beta (TGF-beta) were higher in HFD than in controls. In cardiac myofibroblasts, leptin (10-100 ng/ml) increased O-2(-), collagen I, galectin-3, TGF-beta and connective tissue growth factor production (CTGF). These effects were prevented by the presence of either melatonin (10(-3) mmol/l) or the inhibitor of mTOR, rapamycin (10(-4) mmol/l). Blockage of galectin-3 activity by N-acetyllactosamine (LacNac 10(-3) mmol/l) reduced both collagen I and O-2(.-) production induced by leptin. The p70S6 kinase activation/phosphorylation, the downstream mediator of mTOR, induced by leptin was not modified by melatonin. Leptin reduced the metalloproteinase (MMP) 2 activity and the presence of melatonin, rapamycin or LacNac were unable to prevent it.Conclusion:The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-beta and CTGF through oxidative stress increased by activation of mTOR pathway.