Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg^-1·d^-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg^-1·d^-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGFβ-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.

中文翻译：

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Luteolin-7-diglucuronide减轻小鼠中异丙肾上腺素引起的心肌损伤和纤维化。

心肌损伤和随之而来的纤维化改变损害正常的心脏结构并引起心脏功能障碍。氧化应激已被认为是心脏损伤的发病机制，心脏功能障碍和促进纤维化的关键因素。在当前的研究中，我们调查了可食用植物中天然存在的抗氧化剂木犀草素7-地葡糖醛酸（L7DG）是否可以减轻异丙肾上腺素（ISO）诱导的小鼠心肌损伤和纤维化及其潜在机制。通过注射ISO（5 mg·kg ^-1 ·d ^-1，ip）5或10 d诱发小鼠心肌损伤和纤维化。采用两种治疗方案（预处理和后处理）施用L7DG（5-40 mg·kg ^-1 ·d ^-1），ip）进入小鼠。对小鼠实施安乐死后，心脏切片的形态学检查显示，L7DG预处理和后处理方案均显着减轻了ISO诱导的心肌损伤和纤维化。但是，与后处理方案相比，前处理方案对ISO诱导的心肌纤维化的保护作用更好。此外，L7DG预处理可阻断ISO刺激的编码NADPH氧化酶亚基的基因（Cyba，Cybb，Ncf1，Ncf4和Rac2）的表达，NADPH氧化酶是哺乳动物细胞中氧化剂产生的主要来源。此外，L7DG预处理可显着抑制ISO刺激的胶原蛋白基因Col1a1，Col1a2，Col3a1和Col12a1以及非胶原细胞外基质基因fibrillin-1，弹性蛋白，胶原三螺旋重复序列含有1和结缔组织生长因子。此外，L7DG预处理几乎可以逆转与TGFβ介导的纤维化发生串扰的microRNA的ISO改变表达，包括miR-29c-3p，miR-29c-5p，miR-30c-3p，miR-30c-5p和miR-21 。当前的研究首次证明，L7DG在保护心脏免于发展为ISO诱导的损伤和纤维化方面具有药理作用，证明了进一步评估L7DG作为治疗相关心血管疾病的心脏保护剂的合理性。