Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Ciber de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28222 Madrid, Spain.
Int J Mol Sci. 2022 Jul 22;23(15):8080. doi: 10.3390/ijms23158080.
A proteomic approach was used to characterize potential mediators involved in the improvement in cardiac fibrosis observed with the administration of the mitochondrial antioxidant MitoQ in obese rats. Male Wistar rats were fed a standard diet (3.5% fat; CT) or a high-fat diet (35% fat; HFD) and treated with vehicle or MitoQ (200 μM) in drinking water for 7 weeks. Obesity modulated the expression of 33 proteins as compared with controls of the more than 1000 proteins identified. These include proteins related to endoplasmic reticulum (ER) stress and oxidative stress. Proteomic analyses revealed that HFD animals presented with an increase in cardiac transthyretin (TTR) protein levels, an effect that was prevented by MitoQ treatment in obese animals. This was confirmed by plasma levels, which were associated with those of cardiac levels of both binding immunoglobulin protein (BiP), a marker of ER stress, and fibrosis. TTR stimulated collagen I production and BiP in cardiac fibroblasts. This upregulation was prevented by the presence of MitoQ. In summary, the results suggest a role of TTR in cardiac fibrosis development associated with obesity and the beneficial effects of treatment with mitochondrial antioxidants.
采用蛋白质组学方法来描述可能涉及的中介物，这些中介物参与了肥胖大鼠给予线粒体抗氧化剂 MitoQ 后观察到的心脏纤维化改善。雄性 Wistar 大鼠喂食标准饮食（3.5%脂肪；CT）或高脂肪饮食（35%脂肪；HFD），并在饮用水中用载体或 MitoQ（200 μM）处理 7 周。与对照组的 1000 多种蛋白质相比，肥胖症调节了 33 种蛋白质的表达。这些包括与内质网（ER）应激和氧化应激相关的蛋白质。蛋白质组学分析显示，HFD 动物的心脏转甲状腺素蛋白（TTR）蛋白水平增加，而 MitoQ 处理可预防肥胖动物的这种增加。这一点通过血浆水平得到证实，血浆水平与心脏结合免疫球蛋白蛋白（BiP）水平相关，BiP 是 ER 应激的标志物，与纤维化相关。TTR 刺激心脏成纤维细胞中胶原 I 的产生和 BiP。MitoQ 的存在阻止了这种上调。总之，这些结果表明 TTR 在与肥胖相关的心脏纤维化发展中起作用，以及线粒体抗氧化剂治疗的有益作用。
